rs5015

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000342.4(SLC4A1):c.1249C>T(p.Leu417Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 1,614,124 control chromosomes in the GnomAD database, including 1,543 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.031 ( 89 hom., cov: 31)

Exomes 𝑓: 0.042 ( 1454 hom. )

Consequence

SLC4A1
NM_000342.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.00

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 17-44258019-G-A is Benign according to our data. Variant chr17-44258019-G-A is described in ClinVar as [Benign]. Clinvar id is 255904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44258019-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=2 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0306 (4656/152262) while in subpopulation NFE AF= 0.0433 (2944/68020). AF 95% confidence interval is 0.042. There are 89 homozygotes in gnomad4. There are 2231 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 89 AD,AR,BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A1	NM_000342.4 link	c.1249C>T	p.Leu417Leu	synonymous_variant	Exon 11 of 20	ENST00000262418.12	NP_000333.1	P02730-1
SLC4A1	XM_011525129.3 link	c.1249C>T	p.Leu417Leu	synonymous_variant	Exon 11 of 19		XP_011523431.1
SLC4A1	XM_005257593.6 link	c.1054C>T	p.Leu352Leu	synonymous_variant	Exon 9 of 18		XP_005257650.1	P02730-2
SLC4A1	XM_011525130.2 link	c.1249C>T	p.Leu417Leu	synonymous_variant	Exon 11 of 18		XP_011523432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12 link	c.1249C>T	p.Leu417Leu	synonymous_variant	Exon 11 of 20	1	NM_000342.4	ENSP00000262418.6		P02730-1
SLC4A1	ENST00000399246.3 link	c.777+1243C>T		intron_variant	Intron 9 of 14	5		ENSP00000382190.3		A0A0A0MS98

Frequencies

GnomAD3 genomes

AF:

0.0306

AC:

4661

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00799

Gnomad AMI

AF:

0.0450

Gnomad AMR

AF:

0.0279

Gnomad ASJ

AF:

0.0332

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0330

Gnomad FIN

AF:

0.0519

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.0433

Gnomad OTH

AF:

0.0364

GnomAD3 exomes

AF:

0.0334

AC:

8404

AN:

251372

Hom.:

181

AF XY:

0.0350

AC XY:

4753

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00732

Gnomad AMR exome

AF:

0.0240

Gnomad ASJ exome

AF:

0.0351

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0328

Gnomad FIN exome

AF:

0.0508

Gnomad NFE exome

AF:

0.0420

Gnomad OTH exome

AF:

0.0362

GnomAD4 exome

AF:

0.0418

AC:

61086

AN:

1461862

Hom.:

1454

Cov.:

AF XY:

0.0417

AC XY:

30326

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00672

Gnomad4 AMR exome

AF:

0.0251

Gnomad4 ASJ exome

AF:

0.0361

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.0348

Gnomad4 FIN exome

AF:

0.0505

Gnomad4 NFE exome

AF:

0.0454

Gnomad4 OTH exome

AF:

0.0388

GnomAD4 genome

AF:

0.0306

AC:

4656

AN:

152262

Hom.:

Cov.:

AF XY:

0.0300

AC XY:

2231

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00797

Gnomad4 AMR

AF:

0.0278

Gnomad4 ASJ

AF:

0.0332

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0330

Gnomad4 FIN

AF:

0.0519

Gnomad4 NFE

AF:

0.0433

Gnomad4 OTH

AF:

0.0361

Alfa

AF:

0.0402

Hom.:

181

Bravo

AF:

0.0284

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0439

EpiControl

AF:

0.0407

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 18, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant distal renal tubular acidosis

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary spherocytosis type 4

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hemolytic anemia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

3.5

DANN

Benign

0.69

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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