rs1362648752

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_006005.3(WFS1):c.409_424dup(p.Val142GlyfsTer110) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,589,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

WFS1
NM_006005.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 0.125

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-6289078-A-AGGGCCGTCGCGAGGCT is Pathogenic according to our data. Variant chr4-6289078-A-AGGGCCGTCGCGAGGCT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.409_424dup	p.Val142GlyfsTer110	frameshift_variant	4/8	ENST00000226760.5
WFS1	NM_001145853.1 linkuse as main transcript	c.409_424dup	p.Val142GlyfsTer110	frameshift_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.409_424dup	p.Val142GlyfsTer110	frameshift_variant	4/8	1	NM_006005.3	P2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000439

AC:

AN:

205180

Hom.:

AF XY:

0.0000543

AC XY:

AN XY:

110578

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000134

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:

0.0000560

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000369

AC:

AN:

1436812

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

712300

show subpopulations

Gnomad4 AFR exome

AF:

0.0000605

Gnomad4 AMR exome

AF:

0.000196

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000363

Gnomad4 OTH exome

AF:

0.0000504

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wolfram syndrome 1

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Breda Genetics srl	Apr 30, 2021	The variant c.409_424dup (p.Val142Glyfs110) in the WFS1 gene is reported as pathogenic for Wolfram syndrome 1 and WFS1-related spectrum disorders in ClinVar (Variation ID: 4519), and as pathogenic in the Global Variome shared LOVD database v.3.0. It creates a shift in the reading frame, which is predicted to result in a premature stop codon 110 amino acids downstream and in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant is reported with an estimated allele frequency of 0.0000439 in gnomAD exomes, with no homozygous individuals reported. According to the systematic review conducted by De Heredia et al. (2013) about disease-causing mutations in 412 patients with Wolfram syndrome, the c.409_424dup (p.Val142Glyfs110) is present in about 6.53% of cases (PMID:23429432). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2004	- -
Likely pathogenic, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs1362648752 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 25, 2021	PVS1, PM2, PM3 -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2022	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified in 6.53% of individuals with Wolfram syndrome (de Heredia et al., 2013); This variant is associated with the following publications: (PMID: 17568405, 20738327, 34758253, 15605410, 26875006, 32179840, 32141364, 21602428, 12955714, 27395765, 11161832, 15151504, 21446023, 22238590, 15277431, 33841295, 23429432) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2022	This sequence change creates a premature translational stop signal (p.Val142Glyfs*110) in the WFS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WFS1 are known to be pathogenic (PMID: 12955714). This variant is present in population databases (rs767046229, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive Wolfram syndrome (PMID: 1161832, 26875006, 32141364). This variant is also known as 425ins16. ClinVar contains an entry for this variant (Variation ID: 4519). For these reasons, this variant has been classified as Pathogenic. -

WFS1-Related Spectrum Disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 11, 2019

Across a selection of available literature, the WFS1 c.409_424dupGGCCGTCGCGAGGCTG (p.Val142GlyfsTer110) variant has been identified in in seven individuals with Wolfram syndrome, including in a homozygous state in four individuals from three families and in a compound heterozygous state in three unrelated individuals (Domenech et al. 2004; Chaussenot et al. 2011; Rohayem et al. 2011). A systematic review of disease-causing variants associated with Wolfram syndrome indicated that the p.Val142GlyfsTer110 variant is present in 6.53% of patients and is a common cause of Wolfram syndrome in the Spanish population (de Heredia et al. 2013; Domenech et al. 2004). The variant was absent from 98 control chromosomes and is reported at a frequency of 0.000103 in the Latino population of the Genome Aggregation Database. Based on the collective evidence, the p.Val142GlyfsTer110 variant is classified as pathogenic for WFS1-related spectrum disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Type 2 diabetes mellitus

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomics England Pilot Project, Genomics England

- -

Wolfram syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 10, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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