rs2074108

Positions:

• chr17-44258781-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000342.4(SLC4A1):​c.877-158G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 151,846 control chromosomes in the GnomAD database, including 22,637 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.53 (22637 hom., cov: 31)
• Consequence: SLC4A1 NM_000342.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.319

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-44258781-C-T is Benign according to our data. Variant chr17-44258781-C-T is described in ClinVar as [Benign]. Clinvar id is 1285708.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A1	NM_000342.4	c.877-158G>A		intron_variant		ENST00000262418.12	NP_000333.1
SLC4A1	XM_011525129.3	c.877-158G>A		intron_variant			XP_011523431.1
SLC4A1	XM_005257593.6	c.682-158G>A		intron_variant			XP_005257650.1
SLC4A1	XM_011525130.2	c.877-158G>A		intron_variant			XP_011523432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12	c.877-158G>A		intron_variant		1	NM_000342.4	ENSP00000262418.6
SLC4A1	ENST00000399246.3	c.777+481G>A		intron_variant		5		ENSP00000382190.3

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79830 AN: 151728 Hom.: 22592 Cov.: 31

Gnomad AFR AF: 0.730

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.530

Gnomad EAS AF: 0.742

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.363

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.501

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.526 AC: 79933 AN: 151846 Hom.: 22637 Cov.: 31 AF XY: 0.523 AC XY: 38779 AN XY: 74214

Gnomad4 AFR AF: 0.730

Gnomad4 AMR AF: 0.506

Gnomad4 ASJ AF: 0.530

Gnomad4 EAS AF: 0.742

Gnomad4 SAS AF: 0.372

Gnomad4 FIN AF: 0.363

Gnomad4 NFE AF: 0.431

Gnomad4 OTH AF: 0.500

Alfa AF: 0.443 Hom.: 18360

Bravo AF: 0.547

Asia WGS AF: 0.547 AC: 1904 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.3
DANN	Benign	0.59

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

Other links and lift over

dbSNP: rs2074108; hg19: chr17-42336149; COSMIC: COSV52262820; COSMIC: COSV52262820;