rs121912751

Variant names:

• chr17-44251241-G-T
• rs121912751
• NM_000342.4:c.2573C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_000342.4(SLC4A1):​c.2573C>A​(p.Ala858Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,614,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: SLC4A1 NM_000342.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 8.06
• Publications: 39 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 17-44251241-G-T is Pathogenic according to our data. Variant chr17-44251241-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.2573C>A	p.Ala858Asp	missense_variant	Exon 19 of 20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_011525129.3	c.2483C>A	p.Ala828Asp	missense_variant	Exon 18 of 19		XP_011523431.1
SLC4A1	XM_005257593.6	c.2378C>A	p.Ala793Asp	missense_variant	Exon 17 of 18		XP_005257650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.2573C>A	p.Ala858Asp	missense_variant	Exon 19 of 20	1	NM_000342.4	ENSP00000262418.6
SLC4A1	ENST00000399246.3	c.1475C>A	p.Ala492Asp	missense_variant	Exon 14 of 15	5		ENSP00000382190.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000717 AC: 18 AN: 250988 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461850 Hom.: 0 Cov.: 33 AF XY: 0.0000413 AC XY: 30 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000192 Hom.: 1

Bravo AF: 0.00000378

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal tubular acidosis, distal, 4, with hemolytic anemia Pathogenic:7

Jun 12, 2024

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.2573C>A (p.Ala858Asp) variant in SLC4A1 gene has been previously reported in homozygous and compound heterozygous states in individuals affected with Distal Renal Tubular Acidosis (Shaikh W, et al., 2023; Deejai N, et al., 2022). This variant has been observed to segregate with disease in related individuals. Experimental studies have shown that this missense change affects SLC4A1 function (Ungsupravate D, et al., 2010). The amino acid Ala at position 858 is changed to a Asp changing protein sequence and it might alter its composition and physicochemical properties. For these reasons, this variant has been classified as a Pathogenic. -

Mar 12, 2024

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.007%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.70 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.79 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017771 /PMID: 10926824 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 22126643). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Jul 16, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with distal renal tubular acidosis 4 with haemolytic anaemia (MIM#611590), cryohydrocytosis (MIM#185020), distal renal tubular acidosis (MIM#1179800), ovalocytosis, SA type (MIM#166900) and hereditary spherocytosis (MIM#61265) (PMID: 27058983). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene predominantly lead to autosomal dominant conditions, where biallelic variants result in the more severe phenotype, with no correlation in terms of variant types or location (PMID: 27058983). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to aspartic acid. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (18 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and observed in multiple homozygous and compound heterozygous individuals with distal renal tubular acidosis with haemolytic anaemia. Heterozygous individuals had hypochromia microcytosis and mild acanthocytosis (ClinVar, PMID: 22126643, PMID: 31959358). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

A known missense variant, c.2573C>A p. (Ala858Asp) in exon 19 of SLC4A1 (NM_000342.4) was observed in proband in homozygous state (Fawaz et al., 2012, Marik et al., 2022). On segregation, the variant was observed in heterozygous state in his mother and father. This variant is present in 43 individuals in heterozygous state and absent in homozygous state in the gnomAD (v4.1.0) population database. This variant has been reported in homozygous state in four similarly affected individuals from three unrelated families in our in-house data of 3412 exomes. In silico analysis tools (MutationTaster, REVEL, CADD_phred, and MCAP) predict this variant to be damaging to the SLC4A1 protein function. The clinical features observed in the proband are in concordance with distal renal tubular acidosis 4 with hemolytic anemia. Thus, the above-mentioned variant in homozygous state is interpreted to be the likely cause for the condition observed in proband. -

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

- -

Sep 08, 2021

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant distal renal tubular acidosis Pathogenic:2

Jul 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.2573C>Ap.Ala858Asp variant in SLC4A1 gene has been reported previously in heterozygous or homozygous state in individuals affected with Hemolytic Anemia and Distal Renal Tubular Acidosis Shaikh et al., 2023. Experimental studies have shown that this missense change affects SLC4A1 function Ungsupravate et al., 2010. This variant is reported with the allele frequency of 0.01% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic / Pathogenic multiple submissions. The amino acid Ala at position 858 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala858Asp in SLC4A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence Polyphen - Possibly Damaging, SIFT - Damaging, and MutationTaster - Disease causing automatic predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. -

Aug 15, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Oct 28, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 858 of the SLC4A1 protein (p.Ala858Asp). This variant is present in population databases (rs121912751, gnomAD 0.06%). This missense change has been observed in individuals with autosomal dominant and autosomal recessive distal renal tubular acidosis (dRTA) and hemolytic anemia (PMID: 20151848, 20799361, 22126643, 10926824). Individuals heterozygous for this variant alone have incomplete dRTA and can be asymptomatic until further clinical evaluation (PMID: 10926824, 22126643) while individuals that are either homozygous or compound heterozygous with other pathogenic variants have a more severe complete dRTA and/or hemolytic anemia (PMID: 22126643, 20799361, 10926824). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17771). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC4A1 function (PMID: 19289107, 20151848). For these reasons, this variant has been 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

Apr 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Renal tubular acidosis, distal, 4, with hemolytic anemia;CN280572:Autosomal dominant distal renal tubular acidosis Pathogenic:1

May 01, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

ACMG: PS1, PS3, PM3, PP4 -

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	0.94
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	-0.0091	T
MutationAssessor	Pathogenic	3.5	H;.
PhyloP100		8.1
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.92	P;.
Vest4		0.86
MutPred		0.84		Gain of helix (P = 0.0854);.;
MVP		0.93
MPC		1.2
ClinPred		0.95	D
GERP RS		3.7
Varity_R		0.81
gMVP		0.92
Mutation Taster		=44/56	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912751; hg19: chr17-42328609;