rs104893883

Positions:

• chr4-6302281-T-C

Variant summary

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

The ENST00000226760.5(WFS1):​c.2486T>C​(p.Leu829Pro) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L829L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: WFS1 ENST00000226760.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.48

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 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in ENST00000226760.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 4-6302281-T-C is Pathogenic according to our data. Variant chr4-6302281-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6302281-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.2486T>C	p.Leu829Pro	missense_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.2486T>C	p.Leu829Pro	missense_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.2486T>C	p.Leu829Pro	missense_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1	n.1337+1634A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 99

GnomAD4 genome Cov.: 35

Alfa AF: 0.0000327 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12650912, 20738327, 12955714, 12707188, 12707187, 18776598, 17492394, 19877185, 12181639, 31363008, 11709537, 37121227, 36225977, Zhao2023[paper]) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 829 of the WFS1 protein (p.Leu829Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant deafness or clinical features of autosomal recessive Wolfram syndrome (PMID: 11709537, 17492394, 31363008). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4521). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt WFS1 protein function. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 02, 2016	- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2019

- -

Wolfram syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 03, 2023

Variant summary: WFS1 c.2486T>C (p.Leu829Pro) results in a non-conservative amino acid change located in the Wolframin, OB-fold domain (IPR045461) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248518 control chromosomes (gnomAD). c.2486T>C has been reported in the literature in the heterozygous state in multiple individuals affected Autosomal Dominant Nonsyndromic Sensorineural Heaing Loss (e.g. Bespalova_2001, Sloan-Heggen_2016, Lusk_2020) and in the compound heterozygous state in at least two individuals with Wolfram Syndrome (Lusk_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Autosomal dominant nonsyndromic hearing loss 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.8	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.91		Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);
MVP		1.0
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.99

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: rs104893883; hg19: chr4-6304008;