17-44259879-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000342.4(SLC4A1):c.539G>A(p.Arg180His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,614,046 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. R180C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0048 ( 28 hom. )

Consequence

SLC4A1
NM_000342.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:8O:1

Conservation

PhyloP100: -0.714

Publications

10 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024107307).

BP6

Variant 17-44259879-C-T is Benign according to our data. Variant chr17-44259879-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255914.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00288 (439/152200) while in subpopulation NFE AF = 0.00457 (311/68014). AF 95% confidence interval is 0.00415. There are 0 homozygotes in GnomAd4. There are 211 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 28 AD,AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC4A1	NM_000342.4 link	c.539G>A	p.Arg180His	missense_variant	Exon 7 of 20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_011525129.3 link	c.539G>A	p.Arg180His	missense_variant	Exon 7 of 19		XP_011523431.1
SLC4A1	XM_005257593.6 link	c.344G>A	p.Arg115His	missense_variant	Exon 5 of 18		XP_005257650.1
SLC4A1	XM_011525130.2 link	c.539G>A	p.Arg180His	missense_variant	Exon 7 of 18		XP_011523432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12 link	c.539G>A	p.Arg180His	missense_variant	Exon 7 of 20	1	NM_000342.4	ENSP00000262418.6
SLC4A1	ENST00000399246.3 link	c.539G>A	p.Arg180His	missense_variant	Exon 7 of 15	5		ENSP00000382190.3

Frequencies

GnomAD3 genomes

AF:

0.00289

AC:

439

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00457

Gnomad OTH

AF:

0.00241

GnomAD2 exomes

AF:

0.00342

AC:

860

AN:

251454

AF XY:

0.00345

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00243

Gnomad ASJ exome

AF:

0.00962

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00490

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00479

AC:

7003

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00475

AC XY:

3453

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

33480

American (AMR)

AF:

0.00246

AC:

110

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00945

AC:

247

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39698

South Asian (SAS)

AF:

0.00268

AC:

231

AN:

86256

European-Finnish (FIN)

AF:

0.000843

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00547

AC:

6080

AN:

1111986

Other (OTH)

AF:

0.00381

AC:

230

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

423

846

1269

1692

2115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

244

488

732

976

1220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00288

AC:

439

AN:

152200

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

211

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41514

American (AMR)

AF:

0.00216

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00836

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00270

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00457

AC:

311

AN:

68014

Other (OTH)

AF:

0.00238

AC:

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00343

Hom.:

Bravo

AF:

0.00323

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00593

AC:

ExAC

AF:

0.00355

AC:

431

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00534

EpiControl

AF:

0.00504

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC4A1: BP4, BS1, BS2 -

Jan 26, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2, PM1 -

not specified

Uncertain:1Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in one patient with spherocytosis (Van Zweiten 2013). MAF 0.5%. -

Autosomal dominant distal renal tubular acidosis

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. -

Renal tubular acidosis, distal, 4, with hemolytic anemia;CN280572:Autosomal dominant distal renal tubular acidosis

Uncertain:1

May 01, 2025

Rare Kidney Stone Consortium and the Mayo Clinic Hyperoxaluria Center, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

ACMG: PS1, BS1 -

Hereditary spherocytosis type 4

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Hemolytic anemia

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary spherocytosis type 4;C5436235:Renal tubular acidosis, distal, 4, with hemolytic anemia;CN280572:Autosomal dominant distal renal tubular acidosis

Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

4.5

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.65

T;T

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.57

N;.

PhyloP100

-0.71

PrimateAI

Benign

0.29

PROVEAN

Benign

0.29

N;.

REVEL

Uncertain

0.51

Sift

Benign

0.21

T;.

Sift4G

Benign

0.18

T;T

Polyphen

0.0

B;.

Vest4

0.17

MVP

0.98

MPC

0.43

ClinPred

0.00015

GERP RS

-2.0

Varity_R

0.11

gMVP

0.38

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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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