NM_006005.3:c.225C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006005.3(WFS1):c.225C>T(p.Asp75Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000672 in 1,559,792 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 1 hom., cov: 34)

Exomes 𝑓: 0.00039 ( 5 hom. )

Consequence

WFS1
NM_006005.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.74

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:

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=-0.79).

BP6

Variant 4-6277680-C-T is Benign according to our data. Variant chr4-6277680-C-T is described in ClinVar as [Benign]. Clinvar id is 166569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6277680-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.74 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00328 (499/152330) while in subpopulation AFR AF= 0.0114 (473/41580). AF 95% confidence interval is 0.0105. There are 1 homozygotes in gnomad4. There are 227 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3 link	c.225C>T	p.Asp75Asp	synonymous_variant	Exon 2 of 8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 link	c.225C>T	p.Asp75Asp	synonymous_variant	Exon 2 of 8		NP_001139325.1	O76024A0A0S2Z4V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 link	c.225C>T	p.Asp75Asp	synonymous_variant	Exon 2 of 8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.00328

AC:

499

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.000680

AC:

110

AN:

161664

Hom.:

AF XY:

0.000437

AC XY:

AN XY:

86890

show subpopulations

Gnomad AFR exome

AF:

0.0115

Gnomad AMR exome

AF:

0.0000774

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000855

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000638

Gnomad OTH exome

AF:

0.000439

GnomAD4 exome

AF:

0.000390

AC:

549

AN:

1407462

Hom.:

Cov.:

AF XY:

0.000318

AC XY:

221

AN XY:

695024

show subpopulations

Gnomad4 AFR exome

AF:

0.0139

Gnomad4 AMR exome

AF:

0.000216

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000250

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000406

Gnomad4 OTH exome

AF:

0.000823

GnomAD4 genome

AF:

0.00328

AC:

499

AN:

152330

Hom.:

Cov.:

AF XY:

0.00305

AC XY:

227

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0114

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00159

Hom.:

Bravo

AF:

0.00388

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asp75Asp in Exon 02 of WFS1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue, is not located within t he splice consensus sequence, and has been identified in 0.9% (32/3598) of Afric an American chromosomes from a broad population by the NHLBI Exome Sequencing Pr oject (http://evs.gs.washington.edu/EVS; dbSNP rs35216268). -

Apr 09, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:3

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

WFS1-Related Spectrum Disorders

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Wolfram syndrome 1

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs35216268 in Wolfram's syndrome yet. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.1

DANN

Benign

0.79

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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