rs121912745

chr17-44255708-G-Achr17-44255708-G-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.1765C>T(p.Arg589Cys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R589H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC4A1 NM_000342.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 6.61

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 chr17-44255707-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 17-44255708-G-A is Pathogenic according to our data. 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. Variant chr17-44255708-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A1	NM_000342.4	c.1765C>T	p.Arg589Cys	missense_variant	14/20	ENST00000262418.12
SLC4A1	XM_011525129.3	c.1765C>T	p.Arg589Cys	missense_variant	14/19
SLC4A1	XM_005257593.6	c.1570C>T	p.Arg524Cys	missense_variant	12/18
SLC4A1	XM_011525130.2	c.1765C>T	p.Arg589Cys	missense_variant	14/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A1	ENST00000262418.12	c.1765C>T	p.Arg589Cys	missense_variant	14/20	1	NM_000342.4	P1
SLC4A1	ENST00000399246.3	c.778-487C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant distal renal tubular acidosis Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1997	- -
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	- -
Likely pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89; 3Cnet: 0.41). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017764 / PMID: 9312167). Different missense changes at the same codon (p.Arg589His, p.Arg589Leu, p.Arg589Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000017763, VCV000017766 / PMID: 34746046, 9312167, 9600966 / 3billion dataset). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	SLC4A1: PM1, PM2, PM5, PP4:Moderate, PS4:Moderate -
Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2019	Identified in the heterozygous state in multiple patients with autosomal dominant distal renal tubular acidosis tested at GeneDx and in published literature (Forni et al., 2017); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33226606, 33095447, 31672324, 12750988, 28542241, 11934690, 9312167, 29627839, 11149111) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 21, 2021	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 determined to be pathogenic (PMID: 9312167, 16420521, 29627839, 30230413). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 17764). This missense change has been observed in individuals with autosomal dominant SLC4A1-related conditions (PMID: 12750988, 28233610, 28542241, 29627839). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 589 of the SLC4A1 protein (p.Arg589Cys). -

Renal tubular acidosis Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

Jun 07, 2018

This individual is heterozygous for the c.1765C>T variant in the SLC4A1 gene. This variant has been previously described in patients with autosomal dominant distal renal tubular acidosis (AD dRTA), with at least one case found to be de novo in origin (Bruce et al 1997 J Clin Invest 100: 1693-1707; Sritippayawan et al 2003 Pediatr Nephrol 18: 644-648). The p.Arg589 residue in SLC4A1, also known as AE1, is a mutation hotspot with other missense variants at p.Arg589 reported in patients with AD dRTA (e.g. Karet et al Proc. Natl. Acad. Sci. USA 95:6337-6342). The variant has not been reported in any population databases (i.e. gnomAd, ExAC, ESP or dbSNP). In silico analysis of pathogenicity (through Alamut Visual v2.8.1) using PolyPhen2, SIFT and MutationTaster suggest that this variant is likely to be pathogenic. This variant is considered to be pathogenic according to the ACMG guidelines. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.94		Loss of MoRF binding (P = 0.0069);
MVP		0.93
MPC		1.3
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.89

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: rs121912745; hg19: chr17-42333076; COSMIC: COSV99293236; COSMIC: COSV99293236;