rs56072215

Positions:

chr4-6300818-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006005.3(WFS1):c.1023C>T(p.Phe341=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0684 in 1,613,996 control chromosomes in the GnomAD database, including 4,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.050 ( 303 hom., cov: 32)

Exomes 𝑓: 0.070 ( 4075 hom. )

Consequence

WFS1
NM_006005.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.550

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 4-6300818-C-T is Benign according to our data. Variant chr4-6300818-C-T is described in ClinVar as [Benign]. Clinvar id is 45428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6300818-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.55 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0726 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.1023C>T	p.Phe341=	synonymous_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1 linkuse as main transcript	c.1023C>T	p.Phe341=	synonymous_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.1023C>T	p.Phe341=	synonymous_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+3097G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0498

AC:

7581

AN:

152108

Hom.:

304

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0135

Gnomad AMI

AF:

0.177

Gnomad AMR

AF:

0.0484

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0631

Gnomad FIN

AF:

0.0236

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0743

Gnomad OTH

AF:

0.0537

GnomAD3 exomes

AF:

0.0542

AC:

13625

AN:

251454

Hom.:

482

AF XY:

0.0568

AC XY:

7719

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0119

Gnomad AMR exome

AF:

0.0336

Gnomad ASJ exome

AF:

0.0937

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.0615

Gnomad FIN exome

AF:

0.0284

Gnomad NFE exome

AF:

0.0742

Gnomad OTH exome

AF:

0.0624

GnomAD4 exome

AF:

0.0703

AC:

102751

AN:

1461770

Hom.:

4075

Cov.:

AF XY:

0.0704

AC XY:

51173

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.0129

Gnomad4 AMR exome

AF:

0.0349

Gnomad4 ASJ exome

AF:

0.0938

Gnomad4 EAS exome

AF:

0.000378

Gnomad4 SAS exome

AF:

0.0629

Gnomad4 FIN exome

AF:

0.0296

Gnomad4 NFE exome

AF:

0.0779

Gnomad4 OTH exome

AF:

0.0650

GnomAD4 genome

AF:

0.0498

AC:

7581

AN:

152226

Hom.:

303

Cov.:

AF XY:

0.0472

AC XY:

3512

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.0135

Gnomad4 AMR

AF:

0.0482

Gnomad4 ASJ

AF:

0.103

Gnomad4 EAS

AF:

0.00136

Gnomad4 SAS

AF:

0.0634

Gnomad4 FIN

AF:

0.0236

Gnomad4 NFE

AF:

0.0743

Gnomad4 OTH

AF:

0.0531

Alfa

AF:

0.0672

Hom.:

218

Bravo

AF:

0.0507

Asia WGS

AF:

0.0230

AC:

AN:

3476

EpiCase

AF:

0.0792

EpiControl

AF:

0.0785

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Phe341Phe in Exon 08 of WFS1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 7.1% (496/7020) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs56072215). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

Wolfram syndrome 1

Benign:1

Benign, 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. rs56072215 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -

Autosomal dominant nonsyndromic hearing loss 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

4.1

DANN

Benign

0.74

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over