rs200672755

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_006005.3(WFS1):c.2020G>A(p.Gly674Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,613,160 control chromosomes in the GnomAD database, including 1 homozygotes. 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. G674E) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10U:2

Conservation

PhyloP100: 9.40

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain 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 chr4-6301816-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2203527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.867

PP5

Variant 4-6301815-G-A is Pathogenic according to our data. Variant chr4-6301815-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215394.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=5, Pathogenic=3, Uncertain_significance=2}. Variant chr4-6301815-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.2020G>A	p.Gly674Arg	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1 linkuse as main transcript	c.2020G>A	p.Gly674Arg	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.2020G>A	p.Gly674Arg	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+2100C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000243

AC:

AN:

250558

Hom.:

AF XY:

0.000288

AC XY:

AN XY:

135488

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000571

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000318

AC:

464

AN:

1460802

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

244

AN XY:

726764

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.000382

Gnomad4 NFE exome

AF:

0.000351

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.000158

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000331

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 674 of the WFS1 protein (p.Gly674Arg). This variant is present in population databases (rs200672755, gnomAD 0.04%). This missense change has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 22238590, 25211237, 31391115). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215394). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2023	Reported in a family with moderate non-syndromic hearing loss, did not appear to segregate completely with hearing loss in the family and the pathogenicity was described as unclear (Hkli et al., 2014); 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: 23429432, 22238590, 29563951, 27395765, 31264968, 11317350, 28802351, 12955714, 12073007, 31343797, 31391115, 31589614, 33841295, 34792487, 36208030, 34789499, 36147510, 25211237, 26435059, 33538814, 34573359, 31765440, 31850070, 11161832, 36098976, 24909696) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -

Wolfram syndrome 1

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 19, 2022	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Nov 25, 2021	Jewish Algerian origin. Compound heterozygossity with NM_006005.3:c.1088A>C. Congenital low-tone HL. Teenage onset mild vision problem. -

WFS1-Related Spectrum Disorders

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 03, 2017

- -

WFS1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2023

The WFS1 c.2020G>A variant is predicted to result in the amino acid substitution p.Gly674Arg. This variant has been reported in the compound heterozygous state in three patients with optic atrophy, two of which had a likely pathogenic truncating variant on the opposite allele (Table S2, Charif et al. 2021. PubMed ID: 33841295), as well as in the compound heterozygous state along with a likely pathogenic frameshift variant in a patient with Wolfram syndrome (Aloi et al. 2012. PubMed ID: 22238590). This variant has also been reported in the homozygous state in a patient with Wolfram syndrome (Galvez-Ruiz et al. 2017. PubMed ID: 29563951), and in the compound heterozygous state along with a potentially pathogenic missense variant in three patients with Wolfram syndrome from two different families (Zhang et al. 2019. PubMed ID: 31391115). This variant has been reported in the heterozygous state along with another potentially pathogenic missense variant in a patient with optic neuropathy (Lin et al. 2021. PubMed ID: 34573359), and a patient with Wolfram syndrome (Matsunaga et al. 2014. PubMed ID: 25211237), although phase was not reported in these individuals. However, this variant has also been reported in the homozygous state in a presumably unaffected individual of unknown age from a population study (Fattahi et al. 2019. PubMed ID: 31343797), and in the homozygous state in an unaffected individual from a family with Wolfram syndrome (Gómez-Zaera et al. 2001. PubMed ID: 11161832). This variant has been reported in the heterozygous state in three siblings with nonsyndromic hearing loss as well as their unaffected father and two other unaffected siblings (Häkli et al. 2014. PubMed ID: 24909696) and in a patient with type 1 diabetes (Table S6, Yu et al. 2019. PubMed ID: 31264968). Additionally, two different substitutions at the same amino acid position (Glu and Val) have been reported to segregate with autosomal dominant low-frequency sensorineural hearing loss in four and eight affected individuals from two different families, respectively (Cryns et al. 2002. PubMed ID: 12073007). This variant is reported in 0.049% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-6303542-G-A). In ClinVar this variant has conflicting interpretations of uncertain (2), likely pathogenic (5) and pathogenic (2) (https://www.ncbi.nlm.nih.gov/clinvar/variation/215394/). Taken together, we classify this variant as likely pathogenic for autosomal recessive and dominant WFS1-related disease, although penetrance may be incomplete in the homozygous or heterozygous state. -

Diabetes mellitus

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre

PS1 PM2, PM5, PP3 PP5 -

Wolfram-like syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Feb 22, 2024

Criteria applied: PM3_VSTR,PM5_STR,PS4_MOD,PM1,PP3 -

Hearing impairment

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PS1_Strong, PM5_Moderate, PP3_Supporting -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 10, 2018

The p.Gly674Arg variant has been previously reported in an individual with Wolfr am syndrome and an individual with hearing loss (de Heredia 2013, Hakli 2014); h owever, this variant is also present in 0.02% (62/276372) of the total chromosom es in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200672755). Two missense variants at the same position (Gly674Glu and G ly674Val) have been reported to segregate in families with hearing loss (Cryns 2 002). Computational prediction tools and conservation analysis suggest that thi s variant may impact the protein, though this information is not predictive enou gh to determine pathogenicity. In summary, due to conflicting evidence, the clin ical significance of the p.Gly674Arg variant is uncertain. ACMG/AMP Criteria app lied: PP3; PM5; BS1_Supporting. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2020

The c.2020G>A (p.G674R) alteration is located in exon 8 (coding exon 7) of the WFS1 gene. This alteration results from a G to A substitution at nucleotide position 2020, causing the glycine (G) at amino acid position 674 to be replaced by an arginine (R). Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant Wolfram syndrome; however, the clinical significance for autosomal recessive Wolfram syndrome and autosomal dominant hearing loss is unclear. The p.G674R alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.024

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.96

MutPred

0.94

Gain of MoRF binding (P = 0.0328);Gain of MoRF binding (P = 0.0328);

MVP

1.0

ClinPred

0.50

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.43

gMVP

0.92

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