rs121912744

Positions:

• chr17-44255707-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.13

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a transmembrane_region Helical; Name=6 (size 20) in uniprot entity B3AT_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_000342.4
• 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 [Likely_pathogenic]. Clinvar id 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 id is 17763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A1	NM_000342.4	c.1766G>A	p.Arg589His	missense_variant	14/20	ENST00000262418.12
SLC4A1	XM_011525129.3	c.1766G>A	p.Arg589His	missense_variant	14/19
SLC4A1	XM_005257593.6	c.1571G>A	p.Arg524His	missense_variant	12/18
SLC4A1	XM_011525130.2	c.1766G>A	p.Arg589His	missense_variant	14/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A1	ENST00000262418.12	c.1766G>A	p.Arg589His	missense_variant	14/20	1	NM_000342.4	P1
SLC4A1	ENST00000399246.3	c.778-486G>A		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant distal renal tubular acidosis Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	May 26, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Mar 13, 2024	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Cyto-molecular Genetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS), New Delhi	Mar 07, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 27, 2022	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects SLC4A1 function (PMID: 9312167, 16420521). 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. ClinVar contains an entry for this variant (Variation ID: 17763). 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. 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). -
Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 21, 2022	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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 15, 2021

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. -

SLC4A1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2023

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

Pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Oct 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.95		Loss of MoRF binding (P = 0.0097);
MVP		0.94
MPC		1.3
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.85
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs121912744; hg19: chr17-42333075;