4-6302360-A-G

Position:

• chr4-6302360-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000226760.5(WFS1):​c.2565A>G​(p.Ser855Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.699 in 1,612,712 control chromosomes in the GnomAD database, including 397,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S855S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.72 (39478 hom., cov: 36)
  • Exomes 𝑓: 0.70 (357974 hom.)
• Consequence: WFS1 ENST00000226760.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -2.52

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 4-6302360-A-G is Benign according to our data. Variant chr4-6302360-A-G is described in ClinVar as [Benign]. Clinvar id is 45456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6302360-A-G is described in Lovd as [Benign]. Variant chr4-6302360-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-2.52 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.913 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.2565A>G	p.Ser855Ser	synonymous_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.2565A>G	p.Ser855Ser	synonymous_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.2565A>G	p.Ser855Ser	synonymous_variant	8/8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108980 AN: 152142 Hom.: 39427 Cov.: 36

Gnomad AFR AF: 0.758

Gnomad AMI AF: 0.568

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.934

Gnomad SAS AF: 0.774

Gnomad FIN AF: 0.595

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.725

GnomAD3 exomes AF: 0.725 AC: 181149 AN: 249728 Hom.: 66631 AF XY: 0.724 AC XY: 98000 AN XY: 135392

Gnomad AFR exome AF: 0.761

Gnomad AMR exome AF: 0.788

Gnomad ASJ exome AF: 0.789

Gnomad EAS exome AF: 0.932

Gnomad SAS exome AF: 0.766

Gnomad FIN exome AF: 0.603

Gnomad NFE exome AF: 0.675

Gnomad OTH exome AF: 0.718

GnomAD4 exome AF: 0.697 AC: 1018455 AN: 1460452 Hom.: 357974 Cov.: 100 AF XY: 0.699 AC XY: 507815 AN XY: 726564

Gnomad4 AFR exome AF: 0.764

Gnomad4 AMR exome AF: 0.784

Gnomad4 ASJ exome AF: 0.788

Gnomad4 EAS exome AF: 0.958

Gnomad4 SAS exome AF: 0.764

Gnomad4 FIN exome AF: 0.605

Gnomad4 NFE exome AF: 0.678

Gnomad4 OTH exome AF: 0.719

GnomAD4 genome AF: 0.716 AC: 109089 AN: 152260 Hom.: 39478 Cov.: 36 AF XY: 0.715 AC XY: 53236 AN XY: 74446

Gnomad4 AFR AF: 0.758

Gnomad4 AMR AF: 0.756

Gnomad4 ASJ AF: 0.784

Gnomad4 EAS AF: 0.935

Gnomad4 SAS AF: 0.774

Gnomad4 FIN AF: 0.595

Gnomad4 NFE AF: 0.678

Gnomad4 OTH AF: 0.727

Alfa AF: 0.684 Hom.: 9056

Bravo AF: 0.731

EpiCase AF: 0.686

EpiControl AF: 0.692

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2013	- -

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 12107816) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

WFS1-Related Spectrum Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.049
DANN	Benign	0.33
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1046316; hg19: chr4-6304087; COSMIC: COSV56990634; COSMIC: COSV56990634;