4-6300980-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_006005.3(WFS1):c.1185C>T(p.Val395Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 1,613,788 control chromosomes in the GnomAD database, including 297,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.58 ( 26216 hom., cov: 31)

Exomes 𝑓: 0.61 ( 271515 hom. )

Consequence

WFS1
NM_006005.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: -1.57

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 Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 4-6300980-C-T is Benign according to our data. Variant chr4-6300980-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45431.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=9}. Variant chr4-6300980-C-T is described in Lovd as [Benign]. Variant chr4-6300980-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-1.57 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3 link	c.1185C>T	p.Val395Val	synonymous_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 link	c.1185C>T	p.Val395Val	synonymous_variant	Exon 8 of 8		NP_001139325.1	O76024A0A0S2Z4V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 link	c.1185C>T	p.Val395Val	synonymous_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.576

AC:

87402

AN:

151790

Hom.:

26202

Cov.:

show subpopulations

Gnomad AFR

AF:

0.460

Gnomad AMI

AF:

0.389

Gnomad AMR

AF:

0.665

Gnomad ASJ

AF:

0.660

Gnomad EAS

AF:

0.932

Gnomad SAS

AF:

0.643

Gnomad FIN

AF:

0.567

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.593

Gnomad OTH

AF:

0.607

GnomAD3 exomes

AF:

0.635

AC:

159580

AN:

251462

Hom.:

52156

AF XY:

0.634

AC XY:

86110

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.465

Gnomad AMR exome

AF:

0.735

Gnomad ASJ exome

AF:

0.676

Gnomad EAS exome

AF:

0.931

Gnomad SAS exome

AF:

0.636

Gnomad FIN exome

AF:

0.571

Gnomad NFE exome

AF:

0.589

Gnomad OTH exome

AF:

0.633

GnomAD4 exome

AF:

0.605

AC:

884561

AN:

1461880

Hom.:

271515

Cov.:

103

AF XY:

0.606

AC XY:

440770

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.455

Gnomad4 AMR exome

AF:

0.726

Gnomad4 ASJ exome

AF:

0.676

Gnomad4 EAS exome

AF:

0.958

Gnomad4 SAS exome

AF:

0.635

Gnomad4 FIN exome

AF:

0.572

Gnomad4 NFE exome

AF:

0.589

Gnomad4 OTH exome

AF:

0.619

GnomAD4 genome

AF:

0.576

AC:

87441

AN:

151908

Hom.:

26216

Cov.:

AF XY:

0.578

AC XY:

42901

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.460

Gnomad4 AMR

AF:

0.666

Gnomad4 ASJ

AF:

0.660

Gnomad4 EAS

AF:

0.933

Gnomad4 SAS

AF:

0.644

Gnomad4 FIN

AF:

0.567

Gnomad4 NFE

AF:

0.593

Gnomad4 OTH

AF:

0.609

Alfa

AF:

0.593

Hom.:

34050

Bravo

AF:

0.580

Asia WGS

AF:

0.753

AC:

2618

AN:

3478

EpiCase

AF:

0.593

EpiControl

AF:

0.599

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:7

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jul 30, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 28, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:4

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12107816) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Wolfram syndrome 1

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs1801206 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant rs1801206 is yet to be ascertained. -

WFS1-Related Spectrum Disorders

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Autosomal dominant nonsyndromic hearing loss 6

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.83

DANN

Benign

0.68

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