4-6301295-C-T

Position:

• chr4-6301295-C-T

Variant summary

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

The NM_006005.3(WFS1):​c.1500C>T​(p.Asn500Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.625 in 1,610,910 control chromosomes in the GnomAD database, including 319,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.64 (32210 hom., cov: 33)
  • Exomes 𝑓: 0.62 (286987 hom.)
• Consequence: WFS1 NM_006005.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -0.211

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 4-6301295-C-T is Benign according to our data. Variant chr4-6301295-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45437.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=8}. Variant chr4-6301295-C-T is described in Lovd as [Benign]. Variant chr4-6301295-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.211 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.918 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3	c.1500C>T	p.Asn500Asn	synonymous_variant	8/8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.1500C>T	p.Asn500Asn	synonymous_variant	8/8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.1500C>T	p.Asn500Asn	synonymous_variant	8/8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97912 AN: 152012 Hom.: 32162 Cov.: 33

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.701

Gnomad ASJ AF: 0.682

Gnomad EAS AF: 0.940

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.567

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.602

Gnomad OTH AF: 0.656

GnomAD3 exomes AF: 0.665 AC: 165988 AN: 249436 Hom.: 56487 AF XY: 0.662 AC XY: 89435 AN XY: 135040

Gnomad AFR exome AF: 0.673

Gnomad AMR exome AF: 0.751

Gnomad ASJ exome AF: 0.697

Gnomad EAS exome AF: 0.940

Gnomad SAS exome AF: 0.699

Gnomad FIN exome AF: 0.575

Gnomad NFE exome AF: 0.599

Gnomad OTH exome AF: 0.655

GnomAD4 exome AF: 0.623 AC: 909064 AN: 1458780 Hom.: 286987 Cov.: 94 AF XY: 0.625 AC XY: 453566 AN XY: 725876

Gnomad4 AFR exome AF: 0.676

Gnomad4 AMR exome AF: 0.745

Gnomad4 ASJ exome AF: 0.696

Gnomad4 EAS exome AF: 0.962

Gnomad4 SAS exome AF: 0.695

Gnomad4 FIN exome AF: 0.573

Gnomad4 NFE exome AF: 0.598

Gnomad4 OTH exome AF: 0.648

GnomAD4 genome AF: 0.644 AC: 98017 AN: 152130 Hom.: 32210 Cov.: 33 AF XY: 0.646 AC XY: 48027 AN XY: 74362

Gnomad4 AFR AF: 0.670

Gnomad4 AMR AF: 0.701

Gnomad4 ASJ AF: 0.682

Gnomad4 EAS AF: 0.940

Gnomad4 SAS AF: 0.703

Gnomad4 FIN AF: 0.567

Gnomad4 NFE AF: 0.602

Gnomad4 OTH AF: 0.660

Alfa AF: 0.622 Hom.: 48597

Bravo AF: 0.656

Asia WGS AF: 0.818 AC: 2844 AN: 3478

EpiCase AF: 0.606

EpiControl AF: 0.612

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:7

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	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	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2013	- -
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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Type 2 diabetes mellitus Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations of WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However, contradictory evidences are found for rs1801214 role in Diabetes mellitus. -

WFS1-Related Spectrum Disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.31
DANN	Benign	0.43

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: rs1801214; hg19: chr4-6303022;