4-6300980-C-T

Position:

• chr4-6300980-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The ENST00000226760.5(WFS1):​c.1185C>T​(p.Val395=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 1,613,788 control chromosomes in the GnomAD database, including 297,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V395V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.58 (26216 hom., cov: 31)
  • Exomes 𝑓: 0.61 (271515 hom.)
• Consequence: WFS1 ENST00000226760.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: -1.57

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 4-6300980-C-T is Benign according to our data. Variant chr4-6300980-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45431.We mark this variant Likely_benign, oryginal submissions are: {Benign=9, Uncertain_significance=1}. Variant chr4-6300980-C-T is described in Lovd as [Benign]. Variant chr4-6300980-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.1185C>T	p.Val395=	synonymous_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.1185C>T	p.Val395=	synonymous_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.1185C>T	p.Val395=	synonymous_variant	8/8	1	NM_006005.3	ENSP00000226760	P2
	ENST00000661896.1	n.1337+2935G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.576 AC: 87402 AN: 151790 Hom.: 26202 Cov.: 31

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.665

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.932

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.607

GnomAD3 exomes AF: 0.635 AC: 159580 AN: 251462 Hom.: 52156 AF XY: 0.634 AC XY: 86110 AN XY: 135912

Gnomad AFR exome AF: 0.465

Gnomad AMR exome AF: 0.735

Gnomad ASJ exome AF: 0.676

Gnomad EAS exome AF: 0.931

Gnomad SAS exome AF: 0.636

Gnomad FIN exome AF: 0.571

Gnomad NFE exome AF: 0.589

Gnomad OTH exome AF: 0.633

GnomAD4 exome AF: 0.605 AC: 884561 AN: 1461880 Hom.: 271515 Cov.: 103 AF XY: 0.606 AC XY: 440770 AN XY: 727238

Gnomad4 AFR exome AF: 0.455

Gnomad4 AMR exome AF: 0.726

Gnomad4 ASJ exome AF: 0.676

Gnomad4 EAS exome AF: 0.958

Gnomad4 SAS exome AF: 0.635

Gnomad4 FIN exome AF: 0.572

Gnomad4 NFE exome AF: 0.589

Gnomad4 OTH exome AF: 0.619

GnomAD4 genome AF: 0.576 AC: 87441 AN: 151908 Hom.: 26216 Cov.: 31 AF XY: 0.578 AC XY: 42901 AN XY: 74234

Gnomad4 AFR AF: 0.460

Gnomad4 AMR AF: 0.666

Gnomad4 ASJ AF: 0.660

Gnomad4 EAS AF: 0.933

Gnomad4 SAS AF: 0.644

Gnomad4 FIN AF: 0.567

Gnomad4 NFE AF: 0.593

Gnomad4 OTH AF: 0.609

Alfa AF: 0.593 Hom.: 34050

Bravo AF: 0.580

Asia WGS AF: 0.753 AC: 2618 AN: 3478

EpiCase AF: 0.593

EpiControl AF: 0.599

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7

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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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	- -

Wolfram syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs1801206 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant rs1801206 is yet to be ascertained. -

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	-0.58
CADD	Benign	0.83
DANN	Benign	0.68

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: rs1801206; hg19: chr4-6302707; COSMIC: COSV56987540; COSMIC: COSV56987540;