rs74315205

Variant names:

• chr4-6302385-G-A
• rs74315205
• NM_006005.3:c.2590G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-6302385-G-A
• chr4-6302385-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_006005.3(WFS1):​c.2590G>A​(p.Glu864Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 35)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 9.17

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]

ENSG00000286176 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 4-6302385-G-A is Pathogenic according to our data. Variant chr4-6302385-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6302385-G-A is described in Lovd as [Pathogenic]. Variant chr4-6302385-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.2590G>A	p.Glu864Lys	missense_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.2590G>A	p.Glu864Lys	missense_variant	Exon 8 of 8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.2590G>A	p.Glu864Lys	missense_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 87

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 6 Pathogenic:3 Other:1

Feb 19, 2016

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Comgenital, low-tone, U-shaped HL -

May 07, 2018

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Dominant, postlingual, moderate-profound HL, U-shaped audiogram -

Jun 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:3

Dec 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21917145, 34416374, 31389194, 29511163, 34997062, 16648378, 26346818, 29529044, 31600780, 17492394, 32567228, 33841295, 18544103, 28271504) -

Nov 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 864 of the WFS1 protein (p.Glu864Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Wolfram-like syndrome and nonsyndromic deafness (PMID: 16648378, 17492394, 21917145, 29529044). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4526). Invitae Evidence 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 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 WFS1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Wolfram-like syndrome Pathogenic:2

Jun 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 05, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nonsyndromic genetic hearing loss Pathogenic:1

Jul 15, 2021

INGEBI, INGEBI / CONICET

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria::The c.2590 G>A variant (p.Glu864Lys) in WFS1 gene is absent in gnomAD population database meeting PM2. This variant has been identified in six probands with familial autosomal sensorineural hearing loss and the variant segregated correctly in the affected memebers of different families applying to PS4_Mod and PP1_Mod (PMID:16648378, 17492394, 20301750, 21917145, this report). In two familial cases some affected relatives presented optic atrophy and diabetes with variable onset and severity in adittion to hearing impairment. Since hearing loss is the constant feature, the other evidence sypmton is not considered. Computational evidence predicted a pathogenic impacto of the mutation to the protein (PP3). Considering all the information: PM2, PS4_Mod, PP1_Mod and PP3 the c.2590 G>A variant is classified as Likely Pathogenic for autosomal dominant hearing loss (affecting predominantly low frequencies). -

See cases Pathogenic:1

Apr 25, 2024

Institute of Human Genetics, University Hospital Muenster

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG categories: PS4,PM2,PP5_mod -

Wolfram syndrome 1 Pathogenic:1

May 27, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal dominant nonsyndromic hearing loss Pathogenic:1

Nov 08, 2024

Center for Statistical Genetics, Columbia University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Rare genetic deafness Pathogenic:1

Jan 05, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Glu864Lys or c.2590G>A variant in WFS1 has been reported in ten probands with autosomal dominant hearing loss, including three families with Wolfram-like syndrome and one de novo proband. The variant segregated with disease in 15 affected individuals from eight families (Eiberg 2006 PMID: 16648378, Fukuoka 2007 PMID: 17492394, Valero 2008 PMID: 18544103, Brownstein 2011 PMID: 21917145, Moteki 2011 PMID: 26346818, Kobayashi 2018 PMID: 29529044, Guan 2020 PMID: 32567228, LMM data). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss. ACMG/AMP Criteria applied: PS2, PP1_Strong, PM2, PS4_Moderate, BP4. -

Retinal dystrophy Pathogenic:1

Jan 01, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.7	N;N
REVEL	Pathogenic	0.87
Sift	Benign	0.045	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.84		Gain of MoRF binding (P = 0.0016);Gain of MoRF binding (P = 0.0016);
MVP		0.99
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.25
gMVP		0.88

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

Other links and lift over

dbSNP: rs74315205; hg19: chr4-6304112;