Table 3 List of variants detected in genes related to HHA and their ACMG classification scores

Case 1

Hereditary spherocytosis

None

ANK1

c.4585 C > T

p.Arg1529Ter

Hetero

P

PVS1, PM2, PP5

Hereditary spherocytosis

SPTA1

c.5269 C > T

p.Arg1757Cys

Hetero

VOUS

PM2, PP5

Case 2

Hereditary spherocytosis

None

ANK1

c.1737 C > A*

p.Tyr579Ter*

Hetero

LP

PVS1, PM2

Hereditary spherocytosis

Case 3

Hemolytic anemia

None

ANK1

c.2450 C > A

p.Ser817Ter

Hetero

LP

PVS1, PM2

Hereditary spherocytosis

GSR

c.210 C > G

p.Ile70Met

Hetero

VOUS carrier

-

Case 4

Hemolytic anemia

None

ANK1

c.3380del

p.Lys1127SerfsTer19

Hetero

LP

PVS1, PM2

Hereditary spherocytosis

Case 5

Hemolytic anemia

None

ANK1

c.5495 A > T*

p.Asn1832Ile*

Hetero

VOUS

-

Hemolytic anemia

Case 6

Hereditary spherocytosis

Cholecystectomy (mother)

SPTB

c.2163_2164dup*

p.Ser722CysfsTer8*

Hetero

LP

PVS1, PM2

Hereditary spherocytosis

Case 7

Congenital hemolytic anemia

Hemolytic anemia (father)

SPTB

c.149-8_154delinsTGG

Hetero

LP

PVS1, PM2

Hereditary spherocytosis

Case 8

Hereditary spherocytosis

Hereditary spherocytosis (mother)

SPTB

c.3916 C > T

p.Arg1306Ter

Hetero

P

PVS1, PM2, PP5

Hereditary spherocytosis

PIEZO1

c.5134G > C

p.Val1712Leu

Hetero

VOUS

PM2, BP4

Case 9

Congenital hemolytic anemia

Splenectomy and cholecystectomy (father)

SPTB

c.3855 + 1G > T

Hetero

LP

PVS1, PM2

Hereditary spherocytosis

GPI

c.283-2 A > G*

Hetero

LP carrier

PVS1, PM2

Case 10

Hemolytic anemia

None

SPTB

c.3855 + 2T > C

Hetero

LP

PVS1, PM2

Hereditary spherocytosis

Case 11

Hemolytic anemia

Cholecystectomy (grandmother)

SPTA1

c.83G > A

p.Arg28His

Hetero

LP

PS3, PP1, PP5

Hemolytic anemia

PIEZO1

c.3198T > A*

p.Asp1066Glu*

Hetero

VOUS

PM2

Case 12

Beta thalassemia

Anemia (cousin)

HBA1, HBA2

Whole gene deletion

Hetero

P

Alpha thalassemia

Case 13

Hemolytic anemia

None

HBA1, HBA2

Whole gene deletion

Hetero

P

Alpha thalassemia, dehydrated hereditary stomatocytosis

PIEZO1

c.7367G > A

p.Arg2456His

Hetero

LP

PS3, PM2, PP3

Case 14

Anemia

None

HBA2

Whole gene deletion

Hetero

LP

Anemia

Case 15

Hemolytic disease of fetus and newborn

Carrier of PKLR variant (mother and father)

PKLR

c.1618G > T

p.Gly540Ter

Hetero

LP

PVS1, PM2

Anemia pyruvate kinase deficiency

c.1102G > T

p.Val368Phe

Hetero

VOUS

PM2, PP3

SPTB

c.1094T > G*

p.Leu365Arg*

Hetero

VOUS

PM2, PP3

Case 16

Anemia

None

G6PD

c.1478G > A

p.Arg493His

Hemi

P

PS3, PM2, PS4_M, PP1, PP4, PP5

G6PD deficiency anemia

Case 17

Neutropenia

None

G6PD

c.563 C > T

p.Ser188Phe

Hemi

P

PS3, PP5_S

G6PD deficiency anemia

GSR

c.94G > T

p.Glu32Ter

Hetero

LP carrier

PVS1, PM2

PIEZO1

c.5008G > C*

p.Gly1670Arg*

Hetero

VOUS

PM2

c.4499G > A

p.Arg1500Gln

Hetero

VOUS

BP4

Case 18

Anemia

None

ALAS2

c.1355G > A

p.Arg452His

Hemi

LP

PS3, PM2, PP5

Sex-linked hypochromic sideroblastic anemia

SPTA1

c.3668G > A

p.Arg1223Gln

Hetero

VOUS

-

GPI

c.893 C > T*

p.Ser298Leu*

Hetero

VOUS

-

Case 19

Acquired hemolytic anemia

None

PIEZO1

c.3925 C > T

p.His1309Tyr

Hetero

VOUS

-

Acquired hemolytic anemia

Case 20

Hemolytic anemia

Splenectomy (mother)

SLC4A1

c.1476G > C*

p.Trp492Cys*

Hetero

VOUS

PM2, PP3

Hereditary spherocytosis

Jaundice, anemia (mother, maternal grandmother, and aunt)

c.1447G > A

p.Gly483Ser

Hetero

VOUS

-

Case 21

End stage renal disease

None

PKLR

c.1468 C > T

p.Arg490Trp

Hetero

VOUS

-

End stage renal disease

Case 22

Beta thalassemia

None

SLC4A1

c.1310T > C*

p.Val437Ala*

Hetero

VOUS

PM2, PP3

Anemia

Case 23

Anemia, iron deficiency

Anemia (mother, maternal grandfather)

HBB

c.2T > G

p.Met1?

Hetero

P

PS3, PM2, PP5

Hemolytic anemia