rs2285644

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000342.4(SLC4A1):c.2561C>T(p.Pro854Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,614,206 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 76 hom. )

Consequence

SLC4A1
NM_000342.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:9

Conservation

PhyloP100: -0.155

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024487436).

BP6

Variant 17-44251253-G-A is Benign according to our data. Variant chr17-44251253-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 17768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44251253-G-A is described in Lovd as [Pathogenic]. Variant chr17-44251253-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00346 (527/152336) while in subpopulation EAS AF= 0.0247 (128/5186). AF 95% confidence interval is 0.0212. There are 4 homozygotes in gnomad4. There are 269 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR,BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A1	NM_000342.4 linkuse as main transcript	c.2561C>T	p.Pro854Leu	missense_variant	19/20	ENST00000262418.12	NP_000333.1	P02730-1
SLC4A1	XM_011525129.3 linkuse as main transcript	c.2471C>T	p.Pro824Leu	missense_variant	18/19		XP_011523431.1
SLC4A1	XM_005257593.6 linkuse as main transcript	c.2366C>T	p.Pro789Leu	missense_variant	17/18		XP_005257650.1	P02730-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A1	ENST00000262418.12 linkuse as main transcript	c.2561C>T	p.Pro854Leu	missense_variant	19/20	1	NM_000342.4	ENSP00000262418.6		P02730-1
SLC4A1	ENST00000399246.3 linkuse as main transcript	c.1463C>T	p.Pro488Leu	missense_variant	14/15	5		ENSP00000382190.3		A0A0A0MS98

Frequencies

GnomAD3 genomes

AF:

0.00346

AC:

527

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0200

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0246

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000367

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00830

AC:

2086

AN:

251180

Hom.:

AF XY:

0.00655

AC XY:

889

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.000555

Gnomad AMR exome

AF:

0.0415

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0282

Gnomad SAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.000833

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.00473

GnomAD4 exome

AF:

0.00271

AC:

3963

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

1828

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.0386

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0414

Gnomad4 SAS exome

AF:

0.00161

Gnomad4 FIN exome

AF:

0.000805

Gnomad4 NFE exome

AF:

0.000223

Gnomad4 OTH exome

AF:

0.00233

GnomAD4 genome

AF:

0.00346

AC:

527

AN:

152336

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

269

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.0199

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0247

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.00605

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00710

AC:

862

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2020	This variant is associated with the following publications: (PMID: 20825599, 21637597, 17137217, 24724911, 8206915, 19727826) -

Hereditary spherocytosis type 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

DIEGO BLOOD GROUP ANTIGEN

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 10, 1994

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Autosomal dominant distal renal tubular acidosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Hemolytic anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.64

D;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-2.9

D;.

REVEL

Benign

0.21

Sift

Benign

0.040

D;.

Sift4G

Benign

0.073

T;T

Polyphen

0.79

P;.

Vest4

0.28

MVP

0.31

MPC

0.48

ClinPred

0.065

GERP RS

-1.5

Varity_R

0.085

gMVP

0.51

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