17-44254581-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000342.4(SLC4A1):c.1972G>A(p.Glu658Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000322 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E658Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

SLC4A1
NM_000342.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2O:1

Conservation

PhyloP100: -6.30

Publications

11 publications found

Variant links:

Genes affected

SLC4A1 (HGNC:11027): (solute carrier family 4 member 1 (Diego blood group)) The protein encoded by this gene is part of the anion exchanger (AE) family and is expressed in the erythrocyte plasma membrane, where it functions as a chloride/bicarbonate exchanger involved in carbon dioxide transport from tissues to lungs. The protein comprises two domains that are structurally and functionally distinct. The N-terminal 40kDa domain is located in the cytoplasm and acts as an attachment site for the red cell skeleton by binding ankyrin. The glycosylated C-terminal membrane-associated domain contains 12-14 membrane spanning segments and carries out the stilbene disulphonate-sensitive exchange transport of anions. The cytoplasmic tail at the extreme C-terminus of the membrane domain binds carbonic anhydrase II. The encoded protein associates with the red cell membrane protein glycophorin A and this association promotes the correct folding and translocation of the exchanger. This protein is predominantly dimeric but forms tetramers in the presence of ankyrin. Many mutations in this gene are known in man, and these mutations can lead to two types of disease: destabilization of red cell membrane leading to hereditary spherocytosis, and defective kidney acid secretion leading to distal renal tubular acidosis. Other mutations that do not give rise to disease result in novel blood group antigens, which form the Diego blood group system. Southeast Asian ovalocytosis (SAO, Melanesian ovalocytosis) results from the heterozygous presence of a deletion in the encoded protein and is common in areas where Plasmodium falciparum malaria is endemic. One null mutation in this gene is known, resulting in very severe anemia and nephrocalcinosis. [provided by RefSeq, Jul 2008]

SLC4A1 Gene-Disease associations (from GenCC):

autosomal dominant distal renal tubular acidosis
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
hereditary spherocytosis type 4
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
renal tubular acidosis, distal, 4, with hemolytic anemia
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
southeast Asian ovalocytosis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
dehydrated hereditary stomatocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary spherocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cryohydrocytosis
Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

SLC4A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP6

Variant 17-44254581-C-T is Benign according to our data. Variant chr17-44254581-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17759.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Benign=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A1	NM_000342.4 link	c.1972G>A	p.Glu658Lys	missense_variant	Exon 16 of 20	ENST00000262418.12	NP_000333.1	P02730-1
SLC4A1	XM_011525129.3 link	c.1882G>A	p.Glu628Lys	missense_variant	Exon 15 of 19		XP_011523431.1
SLC4A1	XM_005257593.6 link	c.1777G>A	p.Glu593Lys	missense_variant	Exon 14 of 18		XP_005257650.1	P02730-2
SLC4A1	XM_011525130.2 link	c.1972G>A	p.Glu658Lys	missense_variant	Exon 16 of 18		XP_011523432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12 link	c.1972G>A	p.Glu658Lys	missense_variant	Exon 16 of 20	1	NM_000342.4	ENSP00000262418.6		P02730-1
SLC4A1	ENST00000399246.3 link	c.874G>A	p.Glu292Lys	missense_variant	Exon 11 of 15	5		ENSP00000382190.3		A0A0A0MS98

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000199

AC:

AN:

251322

AF XY:

0.000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000330

AC:

482

AN:

1461800

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

234

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.000335

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000139

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000384

AC:

427

AN:

1111956

Other (OTH)

AF:

0.000315

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000243

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000485

AC:

AN:

68018

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000339

Hom.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jul 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Mar 27, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC4A1 c.1972G>A (p.Glu658Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251322 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SLC4A1 causing SLC4A1-Related Disorders, allowing no conclusion about variant significance. c.1972G>A has been reported in the literature in individuals affected with SLC4A1-Related Disorders (Bruce_1995, Alshomar_2024). These reports do not provide unequivocal conclusions about association of the variant with SLC4A1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 38319988, 7812009). ClinVar contains an entry for this variant (Variation ID: 17759). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary spherocytosis type 4

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

BLOOD GROUP--DIEGO SYSTEM;C1832168:BLOOD GROUP--FROESE;C1832169:BLOOD GROUP--SWANN SYSTEM;C1861453:Cryohydrocytosis;C1862190:BLOOD GROUP--WRIGHT ANTIGEN;C1862191:BLOOD GROUP--WALDNER TYPE;C1862322:Southeast Asian ovalocytosis;C1970028:Malaria, susceptibility to;C2675212:Hereditary spherocytosis type 4;C5436235:Renal tubular acidosis, distal, 4, with hemolytic anemia;CN280572:Autosomal dominant distal renal tubular acidosis

Uncertain:1

Apr 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hemolytic anemia

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Autosomal dominant distal renal tubular acidosis

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

BLOOD GROUP--WRIGHT ANTIGEN

Other:1

Jan 15, 1995

OMIM

Significance:Affects

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.25

CADD

Benign

0.0010

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.040

MetaRNN

Uncertain

0.51

D;D

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-0.050

N;.

PhyloP100

-6.3

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.42

N;.

REVEL

Uncertain

0.42

Sift

Benign

0.10

T;.

Sift4G

Benign

0.22

T;T

Polyphen

0.0010

B;.

Vest4

0.30

MVP

0.99

MPC

0.39

ClinPred

0.024

GERP RS

-11

Varity_R

0.22

gMVP

0.43

Mutation Taster

=34/66

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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17-44254581-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over