rs56002719

chr4-6302122-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1 PP3 BP4_Strong BP6_Very_Strong BS2

The NM_006005.3(WFS1):c.2327A>T(p.Glu776Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00424 in 1,612,924 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0043 (28 hom.)
• Consequence: WFS1 NM_006005.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 8.77

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 Benign. 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, 14 uncertain in NM_006005.3
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.066612035).
• BP6: Variant 4-6302122-A-T is Benign according to our data. Variant chr4-6302122-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 166606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6302122-A-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.2327A>T	p.Glu776Val	missense_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1	c.2327A>T	p.Glu776Val	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.2327A>T	p.Glu776Val	missense_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1	n.1337+1793T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152216 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00445

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00380 AC: 941 AN: 247476 Hom.: 2 AF XY: 0.00377 AC XY: 507 AN XY: 134604

Gnomad AFR exome AF: 0.00115

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000818

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.00548

Gnomad OTH exome AF: 0.00411

GnomAD4 exome AF: 0.00433 AC: 6322 AN: 1460590 Hom.: 28 Cov.: 98 AF XY: 0.00419 AC XY: 3046 AN XY: 726594

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00211

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.00480

Gnomad4 OTH exome AF: 0.00419

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152334 Hom.: 3 Cov.: 34 AF XY: 0.00368 AC XY: 274 AN XY: 74488

Gnomad4 AFR AF: 0.000769

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0125

Gnomad4 NFE AF: 0.00445

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00391 Hom.: 0

Bravo AF: 0.00247

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00454 AC: 39

ExAC AF: 0.00409 AC: 496

EpiCase AF: 0.00371

EpiControl AF: 0.00445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:8

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2020	Identified in patients with Wolfram syndrome who harbored a second missense variant in the WFS1 gene in published literature but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Smith et al., 2004; Astuti et al., 2017); This variant is associated with the following publications: (PMID: 21446023, 20981092, 24909696, 15277431, 28432734, 30245029, 31638168) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	WFS1: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 28, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Glu776Val in Exon 08 of WFS1: This variant is not expected to have clinical sign ificance because it has been identified in 0.4% (31/7006) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs56002719). -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 21, 2021	- -

WFS1-Related Spectrum Disorders Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

WFS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Nonsyndromic genetic hearing loss Benign:1

Benign, 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 filter allele frequency of the c.2327A>T in WFS1 gene is 0,5% for european non-finnish and 1% for european finnish (calculatin with 95%CI) in gnomAD database, exceeding the treshold for dominant HL, meeting BA1. Computational analysis predicted a pathogenic effect of the mutation to the protein, REVEL= 0,98 (PP3). Our internal data demonstrated that the variant seggregated with the affected mother and grandother applying for PP1_Sup. However, there is a report in which the variant did not segregate with the pathology in a family (an unaffected sibling and father carried the mutation) meeting BS4. Taking into account the evidence: BA1, PP3, PP1_Sup and BS4 the vartiant is classified as Benign. -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Mar 10, 2017

ACMG Criteria:PP3 (10 predictors), BS1 (1.15% in ExAC Finnish population, 1 homo in ExAC), BS2 (39 cases and 42 controls in type2diabetesgenetics.org) -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
MetaRNN	Benign	0.067	T;T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.98
MVP		1.0
ClinPred		0.024	T
GERP RS		5.5
Varity_R		0.65
gMVP		0.90

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: rs56002719; hg19: chr4-6303849;