Variant rs267607065 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS2_Supporting

The NM_001174089.2(SLC4A11):c.1147G>A(p.Glu383Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,458,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SLC4A11
NM_001174089.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 6.07

Variant links:

Genes affected

SLC4A11 (HGNC:16438): (solute carrier family 4 member 11) This gene encodes a voltage-regulated, electrogenic sodium-coupled borate cotransporter that is essential for borate homeostasis, cell growth and cell proliferation. Mutations in this gene have been associated with a number of endothelial corneal dystrophies including recessive corneal endothelial dystrophy 2, corneal dystrophy and perceptive deafness, and Fuchs endothelial corneal dystrophy. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2010]

SLC4A11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.779

BS2

High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A11	NM_001174089.2 linkuse as main transcript	c.1147G>A	p.Glu383Lys	missense_variant	10/20	ENST00000642402.1	NP_001167560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC4A11	ENST00000642402.1 linkuse as main transcript	c.1147G>A	p.Glu383Lys	missense_variant	10/20		NM_001174089.2	ENSP00000493503	P2	Q8NBS3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

248954

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000896

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1458316

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

725374

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Corneal dystrophy, Fuchs endothelial, 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2006

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 26, 2023

Variant summary: SLC4A11 c.1195G>A (p.Glu399Lys) results in a conservative amino acid change located in the Bicarbonate transporter-like, transmembrane domain (IPR011531) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248954 control chromosomes (gnomAD). c.1195G>A has been reported in the literature in an individual affected with Fuchs endothelial corneal dystrophy. These data suggest the variant may be association with disease. At least two publications report experimental evidence evaluating an impact on protein function, showing reduced expression of mature SLC4A11 protein and disruption of cell surface localization. The following publications have been ascertained in the context of this evaluation (PMID: 18024964, 29327391). No submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 19, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 399 of the SLC4A11 protein (p.Glu399Lys). This variant is present in population databases (rs267607065, gnomAD 0.0009%). This missense change has been observed in individual(s) with Fuchs endothelial dystrophy (PMID: 18024964, 25007886). ClinVar contains an entry for this variant (Variation ID: 1323). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC4A11 protein function. Experimental studies have shown that this missense change affects SLC4A11 function (PMID: 18024964, 22072594, 29327391). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

T;.;.;.;.;.;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

D;D;.;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.78

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.082

MutationAssessor

Uncertain

2.4

M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.90

N;N;.;.;.;.;N

REVEL

Uncertain

0.64

Sift

Benign

0.49

T;T;.;.;.;.;T

Sift4G

Benign

0.45

T;T;.;.;.;.;T

Polyphen

1.0

D;.;.;.;.;.;.

Vest4

0.93

MVP

0.94

MPC

1.0

ClinPred

0.93

GERP RS

5.2

Varity_R

0.31

gMVP

0.93

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