rs121912744

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000342.4(SLC4A1):c.1766G>A(p.Arg589His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R589C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SLC4A1
NM_000342.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 6.13

Publications

43 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: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-44255708-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 17-44255707-C-T is Pathogenic according to our data. Variant chr17-44255707-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 17763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SLC4A1	NM_000342.4 link	c.1766G>A	p.Arg589His	missense_variant	Exon 14 of 20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_011525129.3 link	c.1766G>A	p.Arg589His	missense_variant	Exon 14 of 19		XP_011523431.1
SLC4A1	XM_005257593.6 link	c.1571G>A	p.Arg524His	missense_variant	Exon 12 of 18		XP_005257650.1
SLC4A1	XM_011525130.2 link	c.1766G>A	p.Arg589His	missense_variant	Exon 14 of 18		XP_011523432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12 link	c.1766G>A	p.Arg589His	missense_variant	Exon 14 of 20	1	NM_000342.4	ENSP00000262418.6
SLC4A1	ENST00000399246.3 link	c.778-486G>A		intron_variant	Intron 9 of 14	5		ENSP00000382190.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal dominant distal renal tubular acidosis

Pathogenic:3

Mar 13, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4, PM2, PP3, PM5, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 17763). This variant has been previously reported as causative (PMID:19565014). -

May 26, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 07, 2022

Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Sep 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Experimental studies have shown that this missense change affects SLC4A1 function (PMID: 9312167, 16420521). This missense change has been observed in individual(s) with autosomal dominant familial renal tubular acidosis (PMID: 9312167, 29627839, 30230413). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17763). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC4A1 protein function. This variant is not present in population databases (gnomAD no frequency). This variant disrupts the p.Arg589 amino acid residue in SLC4A1. Other variant(s) that disrupt this residue have been observed in individuals with SLC4A1-related conditions (PMID: 9312167, 29627839), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 589 of the SLC4A1 protein (p.Arg589His). -

Feb 21, 2022

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

DNA sequence analysis of the SLC4A1 gene demonstrated a sequence change, c.1766G>A, in exon 14 that results in an amino acid change, p.Arg589His. This sequence change has not been described in population databases such as ExAC and gnomAD. The p.Arg589His change affects a highly conserved amino acid residue located in a domain of the SLC4A1 protein that is known to be functional. The p.Arg589His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Experimental studies have demonstrated that this sequence change impacts function of the SLC4A1 protein (PMID: 9312167, 164205210). This pathogenic sequence change has previously been described in multiple individuals with distal renal tubular acidosis (PMID: 29627839, 9497368, 30230413, 9312167). Additionally, other missense variants at this same position (p.Arg589Cys, p.Arg589Ser) have been reported individuals with SLC4A1-related disorders (PMID: 11149111, 30256676). Based on these collective evidences, this sequence change is classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Jan 15, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1766G>A (p.R589H) alteration is located in exon 14 (coding exon 13) of the SLC4A1 gene. This alteration results from a G to A substitution at nucleotide position 1766, causing the arginine (R) at amino acid position 589 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the SLC4A1 c.1766G>A alteration was not observed, with coverage at this position. This mutation has been identified in individuals with distal renal tubular acidosis, including one de novo case, and was shown to segregate with disease (Bruce, 1997; Karet, 1998; Bertocchio, 2020). HEK293 and MDCK cells expressing this mutation demonstrated reduced level of cell surface expression (Quilty, 2002; Cordat, 2006). Based on the available evidence, this alteration is classified as pathogenic. -

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

Pathogenic:1

Jun 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SLC4A1-related disorder

Pathogenic:1

Mar 28, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC4A1 c.1766G>A variant is predicted to result in the amino acid substitution p.Arg589His. This variant has been reported to be pathogenic for autosomal dominant distal renal tubular acidosis in several unrelated families (Jarolim et al. 1998. PubMed ID: 9497368; Shayakul et al. 2004. PubMed ID: 14736961; Bruce et al. 1997. PubMed ID: 9312167; Liu J et al 2018. PubMed ID: 30230413). Different changes at the same codon have also been reported to be pathogenic for autosomal dominant distal renal tubular acidosis (p.Arg589Ser in Karet et al.1998. PubMed ID: 9600966; p.Arg589Cys at Bruce et al. 1997. PubMed ID: 9312167). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Distal renal tubular acidosis

Pathogenic:1

Oct 22, 2019

Yale Center for Mendelian Genomics, Yale University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.29

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

3.1

PhyloP100

6.1

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.90

MutPred

0.95

Loss of MoRF binding (P = 0.0097);

MVP

0.94

MPC

1.3

ClinPred

1.0

GERP RS

4.7

Varity_R

0.85

gMVP

0.83

Mutation Taster

=10/90

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over