4-6301848-C-T

Position:

chr4-6301848-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3PP5

The NM_006005.3(WFS1):c.2053C>T(p.Arg685Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,612,938 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R685P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7

Conservation

PhyloP100: 7.45

Variant links:

Genes affected

WFS1 (HGNC:12762): (wolframin ER transmembrane glycoprotein) This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]

WFS1 links:

ENSG00000286176 (HGNC:):

ENSG00000286176 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a topological_domain Lumenal (size 216) in uniprot entity WFS1_HUMAN there are 92 pathogenic changes around while only 24 benign (79%) in NM_006005.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-6301849-G-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.838

PP5

Variant 4-6301848-C-T is Pathogenic according to our data. Variant chr4-6301848-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 393391.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=5, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3 link	c.2053C>T	p.Arg685Cys	missense_variant	8/8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 link	c.2053C>T	p.Arg685Cys	missense_variant	8/8		NP_001139325.1	O76024A0A0S2Z4V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 link	c.2053C>T	p.Arg685Cys	missense_variant	8/8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000212

AC:

AN:

250204

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

135344

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.000555

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000175

AC:

256

AN:

1460664

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

126

AN XY:

726668

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000554

Gnomad4 SAS exome

AF:

0.000371

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000141

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000210

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.000193

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2023	Reported with a second variant (phase unknown) in a patient clinically suspected to have monogenic diabetes in published literature (Colclough et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11920861, 34789499) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 685 of the WFS1 protein (p.Arg685Cys). This variant is present in population databases (rs112967046, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of autosomal recessive WFS1-related conditions (PMID: 34789499). ClinVar contains an entry for this variant (Variation ID: 393391). 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) performed at Invitae indicates that this missense variant is expected to disrupt WFS1 protein function with a positive predictive value of 95%. 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. -

Type 2 diabetes mellitus;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 11, 2024

- -

Wolfram syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laboratory of Prof. Karen Avraham, Tel Aviv University

Jun 13, 2024

Homozygosity of a very rare variant predicted deleterious by most prediction programs and classified as likely pathogenic by one CLinVar entry. -

WFS1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 30, 2024

The WFS1 c.2053C>T variant is predicted to result in the amino acid substitution p.Arg685Cys. This variant has been reported in the compound heterozygous state along with a truncating variant in a patient with features consistent with Wolfram syndrome (Table S4 and S8, Colclough et al. 2022. PubMed ID: 34789499). This variant was also reported in a study of the relationship between Wolfram syndrome carrier status and suicide (Crawford et al. 2002. PubMed ID: 11920861). A different substitutions at the same codon have been reported in patients with sensorineural hearing loss or early-onset diabetes (p.Arg685Pro, Bramhall et al. 2008. PubMed ID: 18518985; p.Arg685His, Artuso et al. 2015. PubMed ID: 25048417). This variant is reported in 0.056% of alleles in individuals of South Asian descent in gnomAD. While we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Optic atrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2021

- -

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jul 22, 2016

ACMG Criteria: PP3 -

Meniere disease

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Center for Computational Biology & Bioinformatics, University of California, San Diego

Jun 03, 2024

- -

Autosomal dominant nonsyndromic hearing loss 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

Jul 30, 2024

The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v4.0.0 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.80 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.93 (>=0.6, sensitivity 0.72 and precision 0.9)]. Different missense changes at the same codon (p.Arg685His, p.Arg685Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000045446, VCV000215395 / PMID: 18518985). Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.62

D;D

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.0

D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.68

MVP

1.0

ClinPred

0.45

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.50

gMVP

0.79

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