rs2857078

chr17-44252803-A-C

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.2311+315T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.616 in 152,098 control chromosomes in the GnomAD database, including 29,995 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.62 (29995 hom., cov: 32)
• Consequence: SLC4A1 NM_000342.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.230

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=-0.87).
• BP6: Variant 17-44252803-A-C is Benign according to our data. Variant chr17-44252803-A-C is described in ClinVar as [Benign]. Clinvar id is 1181739.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC4A1	NM_000342.4	c.2311+315T>G		intron_variant		ENST00000262418.12
SLC4A1	XM_005257593.6	c.2116+315T>G		intron_variant
SLC4A1	XM_011525129.3	c.2221+315T>G		intron_variant
SLC4A1	XM_011525130.2	c.2311+315T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A1	ENST00000262418.12	c.2311+315T>G		intron_variant		1	NM_000342.4	P1
SLC4A1	ENST00000399246.3	c.1213+315T>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.616 AC: 93655 AN: 151980 Hom.: 29977 Cov.: 32

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.821

Gnomad AMR AF: 0.604

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.236

Gnomad SAS AF: 0.692

Gnomad FIN AF: 0.758

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.691

Gnomad OTH AF: 0.625

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

GnomAD4 genome AF: 0.616 AC: 93721 AN: 152098 Hom.: 29995 Cov.: 32 AF XY: 0.618 AC XY: 45927 AN XY: 74340

Gnomad4 AFR AF: 0.502

Gnomad4 AMR AF: 0.603

Gnomad4 ASJ AF: 0.548

Gnomad4 EAS AF: 0.236

Gnomad4 SAS AF: 0.693

Gnomad4 FIN AF: 0.758

Gnomad4 NFE AF: 0.691

Gnomad4 OTH AF: 0.624

Alfa AF: 0.652 Hom.: 6651

Bravo AF: 0.597

Asia WGS AF: 0.484 AC: 1684 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

Aug 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.25
Dann	Benign	0.54

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: rs2857078; hg19: chr17-42330171;