4-6302385-G-A

Position:

• chr4-6302385-G-A

Variant summary

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

The NM_006005.3(WFS1):​c.2590G>A​(p.Glu864Lys) 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 (★★).

• Frequency: Genomes: not found (cov: 35)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 9.17

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 topological_domain Lumenal (size 216) in uniprot entity WFS1_HUMAN there are 92 pathogenic changes around while only 24 benign (79%) in NM_006005.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• PP5: Variant 4-6302385-G-A is Pathogenic according to our data. Variant chr4-6302385-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6302385-G-A is described in Lovd as [Pathogenic]. Variant chr4-6302385-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.2590G>A	p.Glu864Lys	missense_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.2590G>A	p.Glu864Lys	missense_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.2590G>A	p.Glu864Lys	missense_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1	n.1337+1530C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 87

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 6 Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	May 07, 2018	Dominant, postlingual, moderate-profound HL, U-shaped audiogram -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2008	- -
Pathogenic, no assertion criteria provided	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Feb 19, 2016	Comgenital, low-tone, U-shaped HL -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21917145, 34416374, 31389194, 29511163, 34997062, 16648378, 26346818, 29529044, 31600780, 17492394, 32567228, 33841295, 18544103, 28271504) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 864 of the WFS1 protein (p.Glu864Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Wolfram-like syndrome and nonsyndromic deafness (PMID: 16648378, 17492394, 21917145, 29529044). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4526). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on WFS1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Wolfram-like syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 05, 2022	- -

Nonsyndromic genetic hearing loss Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

INGEBI, INGEBI / CONICET

Jul 15, 2021

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria::The c.2590 G>A variant (p.Glu864Lys) in WFS1 gene is absent in gnomAD population database meeting PM2. This variant has been identified in six probands with familial autosomal sensorineural hearing loss and the variant segregated correctly in the affected memebers of different families applying to PS4_Mod and PP1_Mod (PMID:16648378, 17492394, 20301750, 21917145, this report). In two familial cases some affected relatives presented optic atrophy and diabetes with variable onset and severity in adittion to hearing impairment. Since hearing loss is the constant feature, the other evidence sypmton is not considered. Computational evidence predicted a pathogenic impacto of the mutation to the protein (PP3). Considering all the information: PM2, PS4_Mod, PP1_Mod and PP3 the c.2590 G>A variant is classified as Likely Pathogenic for autosomal dominant hearing loss (affecting predominantly low frequencies). -

Wolfram syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

May 27, 2021

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 05, 2021

The p.Glu864Lys or c.2590G>A variant in WFS1 has been reported in ten probands with autosomal dominant hearing loss, including three families with Wolfram-like syndrome and one de novo proband. The variant segregated with disease in 15 affected individuals from eight families (Eiberg 2006 PMID: 16648378, Fukuoka 2007 PMID: 17492394, Valero 2008 PMID: 18544103, Brownstein 2011 PMID: 21917145, Moteki 2011 PMID: 26346818, Kobayashi 2018 PMID: 29529044, Guan 2020 PMID: 32567228, LMM data). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss. ACMG/AMP Criteria applied: PS2, PP1_Strong, PM2, PS4_Moderate, BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.7	N;N
REVEL	Pathogenic	0.87
Sift	Benign	0.045	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.84		Gain of MoRF binding (P = 0.0016);Gain of MoRF binding (P = 0.0016);
MVP		0.99
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.25
gMVP		0.88

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: rs74315205; hg19: chr4-6304112;