rs45519733

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000342.4(SLC4A1):c.2712C>T(p.Tyr904=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 1,613,578 control chromosomes in the GnomAD database, including 609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 35 hom., cov: 32)

Exomes 𝑓: 0.026 ( 574 hom. )

Consequence

SLC4A1
NM_000342.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.294

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]

SLC4A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 17-44250482-G-A is Benign according to our data. Variant chr17-44250482-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44250482-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.294 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0186 (2831/152310) while in subpopulation NFE AF= 0.0277 (1886/68014). AF 95% confidence interval is 0.0267. There are 35 homozygotes in gnomad4. There are 1374 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 35 AD,AR,BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SLC4A1	NM_000342.4 linkuse as main transcript	c.2712C>T	p.Tyr904=	synonymous_variant	20/20	ENST00000262418.12
SLC4A1	XM_011525129.3 linkuse as main transcript	c.2622C>T	p.Tyr874=	synonymous_variant	19/19
SLC4A1	XM_005257593.6 linkuse as main transcript	c.2517C>T	p.Tyr839=	synonymous_variant	18/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC4A1	ENST00000262418.12 linkuse as main transcript	c.2712C>T	p.Tyr904=	synonymous_variant	20/20	1	NM_000342.4	P1	P02730-1
SLC4A1	ENST00000399246.3 linkuse as main transcript	c.1614C>T	p.Tyr538=	synonymous_variant	15/15	5

Frequencies

GnomAD3 genomes

AF:

0.0186

AC:

2833

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00625

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0178

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0226

Gnomad FIN

AF:

0.0213

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0277

Gnomad OTH

AF:

0.0158

GnomAD3 exomes

AF:

0.0199

AC:

5006

AN:

251174

Hom.:

AF XY:

0.0208

AC XY:

2818

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.00511

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0229

Gnomad FIN exome

AF:

0.0201

Gnomad NFE exome

AF:

0.0281

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.0258

AC:

37648

AN:

1461268

Hom.:

574

Cov.:

AF XY:

0.0257

AC XY:

18713

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.00490

Gnomad4 AMR exome

AF:

0.0118

Gnomad4 ASJ exome

AF:

0.00811

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0240

Gnomad4 FIN exome

AF:

0.0209

Gnomad4 NFE exome

AF:

0.0290

Gnomad4 OTH exome

AF:

0.0204

GnomAD4 genome

AF:

0.0186

AC:

2831

AN:

152310

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1374

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00623

Gnomad4 AMR

AF:

0.0178

Gnomad4 ASJ

AF:

0.00980

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0226

Gnomad4 FIN

AF:

0.0213

Gnomad4 NFE

AF:

0.0277

Gnomad4 OTH

AF:

0.0152

Alfa

AF:

0.0217

Hom.:

Bravo

AF:

0.0171

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0252

EpiControl

AF:

0.0237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

Autosomal dominant distal renal tubular acidosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Hereditary spherocytosis type 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 19, 2021

- -

Hemolytic anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

Cadd

Benign

0.13

Dann

Benign

0.44

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over