rs121909392

Positions:

chr20-3228259-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 10P and 4B. PM1PM5PP3_StrongPP5_ModerateBS2

The NM_001174089.2(SLC4A11):c.2558G>A(p.Arg853His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,460,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R853C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

SLC4A11
NM_001174089.2 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.87

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity S4A11_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001174089.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-3228260-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 20-3228259-C-T is Pathogenic according to our data. Variant chr20-3228259-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1311.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-3228259-C-T is described in Lovd as [Pathogenic].

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC4A11	NM_001174089.2 linkuse as main transcript	c.2558G>A	p.Arg853His	missense_variant, splice_region_variant	19/20	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.2558G>A	p.Arg853His	missense_variant, splice_region_variant	19/20		NM_001174089.2	ENSP00000493503	P2	Q8NBS3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249814

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135566

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:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1460764

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726686

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2021

This sequence change replaces arginine with histidine at codon 869 of the SLC4A11 protein (p.Arg869His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant also falls at the last nucleotide of exon 18, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121909392, ExAC 0.005%). This missense change has been observed in individuals with corneal endothelial dystrophy (PMID: 16825429, 23922488, 26619383). ClinVar contains an entry for this variant (Variation ID: 1311). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SLC4A11 function (PMID: 29327391). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Congenital hereditary endothelial dystrophy of cornea

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

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

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;.;T;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.98

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

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.5

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

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-4.5

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

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0030

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

Polyphen

1.0

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

Vest4

0.94

MutPred

0.94

Loss of catalytic residue at R869 (P = 0.0417);.;.;.;.;.;.;

MVP

0.99

MPC

1.1

ClinPred

0.97

GERP RS

5.4

Varity_R

0.57

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.55

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.55

Position offset: -41

DS_DL_spliceai

0.24

Position offset: 0

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