rs45562031

Positions:

chr17-44261625-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000342.4(SLC4A1):c.118G>A(p.Glu40Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0145 in 1,614,150 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.011 ( 13 hom., cov: 32)

Exomes 𝑓: 0.015 ( 209 hom. )

Consequence

SLC4A1
NM_000342.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:12

Conservation

PhyloP100: 0.681

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:

SLC4A1 (HGNC:):

SLC4A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.044904858).

BP6

Variant 17-44261625-C-T is Benign according to our data. Variant chr17-44261625-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17756.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Pathogenic=1, Benign=8, Likely_pathogenic=1}. Variant chr17-44261625-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0111 (1690/152288) while in subpopulation NFE AF= 0.018 (1224/68002). AF 95% confidence interval is 0.0172. There are 13 homozygotes in gnomad4. There are 744 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 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.118G>A	p.Glu40Lys	missense_variant	4/20	ENST00000262418.12	NP_000333.1	P02730-1
SLC4A1	XM_011525129.3 linkuse as main transcript	c.118G>A	p.Glu40Lys	missense_variant	4/19		XP_011523431.1
SLC4A1	XM_011525130.2 linkuse as main transcript	c.118G>A	p.Glu40Lys	missense_variant	4/18		XP_011523432.1
SLC4A1	XM_005257593.6 linkuse as main transcript	c.-78G>A		5_prime_UTR_variant	2/18		XP_005257650.1	P02730-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC4A1	ENST00000262418.12 linkuse as main transcript	c.118G>A	p.Glu40Lys	missense_variant	4/20	1	NM_000342.4	ENSP00000262418.6	P02730-1
SLC4A1	ENST00000399246.3 linkuse as main transcript	c.118G>A	p.Glu40Lys	missense_variant	4/15	5		ENSP00000382190.3	A0A0A0MS98
SLC4A1	ENST00000471005.5 linkuse as main transcript	n.52G>A		non_coding_transcript_exon_variant	2/4	3
SLC4A1	ENST00000498270.1 linkuse as main transcript	n.399G>A		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1691

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.112

Gnomad AMR

AF:

0.00655

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00904

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0180

Gnomad OTH

AF:

0.00956

GnomAD3 exomes

AF:

0.0105

AC:

2638

AN:

251402

Hom.:

AF XY:

0.0105

AC XY:

1431

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.00642

Gnomad ASJ exome

AF:

0.000893

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00206

Gnomad FIN exome

AF:

0.00896

Gnomad NFE exome

AF:

0.0178

Gnomad OTH exome

AF:

0.0121

GnomAD4 exome

AF:

0.0149

AC:

21724

AN:

1461862

Hom.:

209

Cov.:

AF XY:

0.0145

AC XY:

10530

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00311

Gnomad4 AMR exome

AF:

0.00684

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00243

Gnomad4 FIN exome

AF:

0.0101

Gnomad4 NFE exome

AF:

0.0178

Gnomad4 OTH exome

AF:

0.0121

GnomAD4 genome

AF:

0.0111

AC:

1690

AN:

152288

Hom.:

Cov.:

AF XY:

0.00999

AC XY:

744

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00313

Gnomad4 AMR

AF:

0.00647

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00904

Gnomad4 NFE

AF:

0.0180

Gnomad4 OTH

AF:

0.00946

Alfa

AF:

0.0160

Hom.:

Bravo

AF:

0.0111

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0159

AC:

137

ExAC

AF:

0.0108

AC:

1315

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0150

EpiControl

AF:

0.0162

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 23, 2024	This missense variant also known as Band 3 Montefiore occurs in an acidic region of the N-terminus that contains binding sites for aldolase, phosphofructokinase, glyceraldehyde-3-phosphate dehydrogenase, denatured hemoglobins, and protein 4.2 (PMID:11049968). Functional studies indicate the alteration results in impaired binding to protein 4.2. Introduction of a positive charge by the E40K mutants may serve to disrupt the acidic protein 4.2-binding surface on cdAE1 (PMID:21039340). In a single case report, this mutation was detected in the homozygous state in a patient reported to have moderate and episodic nonimmune hemolytic anemia coincident with pregnancy and splenomegaly, spherocytosis, and increased osmotic fragility with a 88% decrease in protein 4.2. None of the heterozygous relatives were symptomatic and had a normal RBC membrane protein 4.2 content (PMID:8471774). This alteration is common in Europeans (MAF 1.8%) but is found at low frequencies in almost all other populations in gnomAD. Due to insufficient data available to clearly classify this variant as pathogenic or benign, it is categorized as a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2020	This variant is associated with the following publications: (PMID: 33226606, 31723846, 27535533, 27354418, 21039340, 16411779, 9207478, 8471774, 20981092) -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SLC4A1 p.Glu40Lys variant was identified in the literature in a female with episodic hemolytic anemia that was homozygous for the p.E40K variant (Rybicki_1993_8471774). The variant was identified in dbSNP (ID: rs45562031), LOVD 3.0 and ClinVar (classified as likely benign by PreventionGenetics and Illumina, as likely pathogenic by Bioinformatics dept., Datar Cancer Genetics Limited, India and as uncertain signifiicance by ARUP Laboratories and CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 3038 of 282752 chromosomes (17 homozygous) at a frequency of 0.010744 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 2337 of 129084 chromosomes (freq: 0.0181), Other in 90 of 7228 chromosomes (freq: 0.01245), European (Finnish) in 234 of 25114 chromosomes (freq: 0.009318), Latino in 231 of 35438 chromosomes (freq: 0.006518), African in 74 of 24954 chromosomes (freq: 0.002965), South Asian in 63 of 30616 chromosomes (freq: 0.002058) and Ashkenazi Jewish in 9 of 10368 chromosomes (freq: 0.000868), but was not observed in the East Asian population. The p.Glu40 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SLC4A1: BP4, BS1, BS2 -

Hereditary spherocytosis type 4

Pathogenic:1Benign:3

Pathogenic, flagged submission	literature only	OMIM	Apr 15, 1993	- -
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. -
Likely benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The homozygous p.Glu40Lys variant in SLC4A1 has been identified in an individual with a previous splenectomy (PMID: 8471774), but has been identified in >1% of European (non-Finnish) chromosomes and 3 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive spherocytosis. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -

Cryohydrocytosis

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Bioinformatics dept., Datar Cancer Genetics Limited, India

Jun 23, 2017

- -

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. -

SLC4A1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 31, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Distal renal tubular acidosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jun 06, 2023

- -

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

0.076

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

T;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.85

D;D

MetaRNN

Benign

0.045

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.7

M;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.0

N;.

REVEL

Benign

0.21

Sift

Benign

0.20

T;.

Sift4G

Benign

0.49

T;T

Polyphen

0.059

B;.

Vest4

0.30

MPC

0.50

ClinPred

0.017

GERP RS

1.1

Varity_R

0.12

gMVP

0.21

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