rs121912746

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The ENST00000262418.12(SLC4A1):​c.1838C>T​(p.Ser613Phe) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (no stars).

Frequency

Genomes: not found (cov: 31)

Consequence

SLC4A1
ENST00000262418.12 missense

Scores

11
7
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 10.0
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a transmembrane_region Helical; Name=7 (size 20) in uniprot entity B3AT_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000262418.12
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
Variant 17-44255259-G-A is Pathogenic according to our data. Variant chr17-44255259-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17765.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SLC4A1NM_000342.4 linkuse as main transcriptc.1838C>T p.Ser613Phe missense_variant 15/20 ENST00000262418.12 NP_000333.1
SLC4A1XM_005257593.6 linkuse as main transcriptc.1643C>T p.Ser548Phe missense_variant 13/18 XP_005257650.1
SLC4A1XM_011525130.2 linkuse as main transcriptc.1838C>T p.Ser613Phe missense_variant 15/18 XP_011523432.1
SLC4A1XM_011525129.3 linkuse as main transcriptc.1800+414C>T intron_variant XP_011523431.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SLC4A1ENST00000262418.12 linkuse as main transcriptc.1838C>T p.Ser613Phe missense_variant 15/201 NM_000342.4 ENSP00000262418 P1P02730-1
SLC4A1ENST00000399246.3 linkuse as main transcriptc.778-38C>T intron_variant 5 ENSP00000382190

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Autosomal dominant distal renal tubular acidosis Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMOct 01, 1997- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.42
D
BayesDel_noAF
Pathogenic
0.36
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.97
D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Uncertain
0.66
D
MutationAssessor
Pathogenic
3.2
M
MutationTaster
Benign
1.0
A
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-4.0
D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.76
MutPred
0.94
Gain of catalytic residue at P611 (P = 0.1276);
MVP
0.94
MPC
1.2
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.96
gMVP
0.96

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121912746; hg19: chr17-42332627; API