rs863224265

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong

The NM_006005.3(WFS1):c.1243_1245del(p.Val415del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000638 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F414F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

WFS1
NM_006005.3 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.50

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 Pathogenic. Variant got 13 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, 9 uncertain in NM_006005.3

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_006005.3. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 4-6301035-TTCG-T is Pathogenic according to our data. Variant chr4-6301035-TTCG-T is described in ClinVar as [Pathogenic]. Clinvar id is 215406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6301035-TTCG-T 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.1243_1245del	p.Val415del	inframe_deletion	8/8	ENST00000226760.5
WFS1	NM_001145853.1 linkuse as main transcript	c.1243_1245del	p.Val415del	inframe_deletion	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.1243_1245del	p.Val415del	inframe_deletion	8/8	1	NM_006005.3	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+2877_1337+2879del		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251462

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000260

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1461890

Hom.:

AF XY:

0.0000550

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000201

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:

0.0000683

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This variant, c.1243_1245del, results in the deletion of 1 amino acid(s) of the WFS1 protein (p.Val415del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs750767821, gnomAD 0.03%). This variant has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 10521293, 21067485, 27617222, 31600780). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215406). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2022	Published functional studies demonstrate a damaging effect resulting in decreased wolframin expression compared to the wildtype (Rendtorff et al., 2011); In-frame deletion of 1 amino acid in a non-repeat region predicted to critically alter the protein; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21067485, 28432734, 16151413, 21446023, 15277431, 18806274, 21538838, 10521293, 21602428, 8808601, 27617222, 19042979, 23429432, 31600780) -

WFS1-Related Spectrum Disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Mar 05, 2022

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 21538838) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 215406; PMID: 27617222; PMID: 23429432; PMID: 19042979) - PS4. The variant is present at low allele frequencies population databases (rs863224265 – gnomAD 0.0008545%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Val415del) was detected in trans with a pathogenic variant (PMID: 27617222; PMID: 19042979) - PM3. Protein length variants as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants - PM4. The variant co-segregated with disease in multiple affected family members (PMID: 27617222) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic. -

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

Apr 30, 2022

- -

WFS1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2024

The WFS1 c.1243_1245delGTC variant is predicted to result in an in-frame deletion (p.Val415del). This sequence variant has been documented to be causative for Wolfram syndrome (Hardy et al. 1999. PubMed ID: 10521293; Smith et al. 2004. PubMed ID: 15277431; Hansen et al. 2005. PubMed ID: 16151413; Gasparin et al. 2009. PubMed ID: 19042979; Marshall et al. 2013. PubMed ID: 23981289). This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Wolfram syndrome 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2011

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 14, 2017

The p.Val415del variant in WFS1 has been reported in >10 individuals with Wolfra m syndrome (Hardy 1999, Smith 2004, Hansen 2005, Gasparin 2009, Chaussenot 2011, Rohayem 2011, Rendtorff 2011, de Heredia ML 2013, Bodoor 2016) and segregated i n 7 affected relatives (Hardy 1999, Hansen 2005, Gasparin 2009, Rendtorff 2011, Bodoor 2016). All of these individuals were homozygous or compound heterozygous. This variant has also been reported in ClinVar (Variation ID: 215406). This var iant was identified in 9/33582 Latino chromosomes by the Genome Aggregation Data base (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750767821); however, its frequency is low enough to be consistent with a recessive carrier frequency. In addition, in vitro studies suggest that the p.Val415del variant may impact expr ession of WFS1 (Rendtorff 2011). In summary, this variant meets criteria to be c lassified as pathogenic for autosomal recessive Wolfram syndrome based upon repo rted familial cases, low frequency in controls, and functional evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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