rs143064649

chr4-6301634-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006005.3(WFS1):c.1839G>A(p.Trp613Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000103 in 1,461,754 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: WFS1 NM_006005.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.87

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 213 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-6301634-G-A is Pathogenic according to our data. Variant chr4-6301634-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 349320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6301634-G-A is described in Lovd as [Pathogenic]. Variant chr4-6301634-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.1839G>A	p.Trp613Ter	stop_gained	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.1839G>A	p.Trp613Ter	stop_gained	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.1839G>A	p.Trp613Ter	stop_gained	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+2281C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251334 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461754 Hom.: 0 Cov.: 98 AF XY: 0.00000688 AC XY: 5 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2022	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 278 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 33538814, 28559085, 12955714, 26025012, 24890733, 23981289) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 349320). This premature translational stop signal has been observed in individuals with Wolfram syndrome (PMID: 12955714, 23981289, 28559085). This variant is present in population databases (rs143064649, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Trp613*) in the WFS1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 278 amino acid(s) of the WFS1 protein. -

WFS1-Related Spectrum Disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 20, 2016

The WFS1 c.1839G>A (p.Trp613Ter) stop-gained variant has been reported in four studies in which it is found in a compound heterozygous state with a second variant in four individuals with Wolfram syndrome (Cryns et al. 2003; Marshall et al. 2013; Chaussenot et al. 2015; Bischoff et al. 2015). Of note, five additional affected individuals were compound heterozygous for a different nucleotide change, c.1838G>A, that results in the same stop-gained variant at codon 613 (p.Trp613Ter). The p.Trp613Ter variant was absent from a total of 100 controls and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project, but this is based on only one allele in a region of good sequence coverage so it is presumed to be rare. Based on the potential impact of stop-gained variants and the evidence from the literature, the p.Trp613Ter 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;C1833021:Autosomal dominant nonsyndromic hearing loss 6;C3280358:Wolfram-like syndrome;C3805412:Cataract 41;C4551693:Wolfram syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 31, 2022

- -

Diabetes mellitus Pathogenic:1

Pathogenic, no assertion criteria provided

research

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

-

PVS1 PS1 PM1 PM2 PP3 PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	49
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
Vest4		0.87
GERP RS		4.5

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: rs143064649; hg19: chr4-6303361;