17-44250482-G-C

Variant names:

• chr17-44250482-G-C
• NM_000342.4:c.2712C>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000342.4(SLC4A1):​c.2712C>G​(p.Tyr904*) variant causes a stop gained change involving the alteration of a non-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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y904Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC4A1 NM_000342.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.294

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00877 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44250482-G-C is Pathogenic according to our data. Variant chr17-44250482-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3236234.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.2712C>G	p.Tyr904*	stop_gained	Exon 20 of 20	ENST00000262418.12	NP_000333.1
SLC4A1	XM_011525129.3	c.2622C>G	p.Tyr874*	stop_gained	Exon 19 of 19		XP_011523431.1
SLC4A1	XM_005257593.6	c.2517C>G	p.Tyr839*	stop_gained	Exon 18 of 18		XP_005257650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.2712C>G	p.Tyr904*	stop_gained	Exon 20 of 20	1	NM_000342.4	ENSP00000262418.6
SLC4A1	ENST00000399246.3	c.1614C>G	p.Tyr538*	stop_gained	Exon 15 of 15	5		ENSP00000382190.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant distal renal tubular acidosis Pathogenic:1

Apr 26, 2023

MVZ Medizinische Genetik Mainz

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG Criteria: PVS1_STR,PM2_SUP,PP4 -

not provided Pathogenic:1

Feb 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr904*) in the SLC4A1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 8 amino acid(s) of the SLC4A1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC4A1-related conditions. This variant is located in a region of the SLC4A1 protein where a significant number SLC4A1 nonsense and frameshift mutations have been reported in association with autosomal dominant distal renal tubular acidosis (PMID: 9600966, 20960171, 31672324, 35738466). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	23
DANN	Benign	0.87
Eigen	Benign	-0.70
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.52	D
Vest4		0.66
GERP RS		-7.2

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-42327850;