rs1046322

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006005.3(WFS1):c.*253G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 597,980 control chromosomes in the GnomAD database, including 3,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.097 ( 794 hom., cov: 33)

Exomes 𝑓: 0.11 ( 2923 hom. )

Consequence

WFS1
NM_006005.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.00

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 4-6302721-G-A is Benign according to our data. Variant chr4-6302721-G-A is described in ClinVar as [Benign]. Clinvar id is 349340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.115 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.*253G>A		3_prime_UTR_variant	8/8	ENST00000226760.5
WFS1	NM_001145853.1 linkuse as main transcript	c.*253G>A		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.*253G>A		3_prime_UTR_variant	8/8	1	NM_006005.3	P2
	ENST00000661896.1 linkuse as main transcript	n.1337+1194C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0973

AC:

14804

AN:

152194

Hom.:

795

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0654

Gnomad AMI

AF:

0.200

Gnomad AMR

AF:

0.0871

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.0697

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.0865

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.117

Gnomad OTH

AF:

0.106

GnomAD4 exome

AF:

0.110

AC:

48995

AN:

445668

Hom.:

2923

Cov.:

AF XY:

0.111

AC XY:

25653

AN XY:

232038

show subpopulations

Gnomad4 AFR exome

AF:

0.0684

Gnomad4 AMR exome

AF:

0.0725

Gnomad4 ASJ exome

AF:

0.126

Gnomad4 EAS exome

AF:

0.0743

Gnomad4 SAS exome

AF:

0.117

Gnomad4 FIN exome

AF:

0.0891

Gnomad4 NFE exome

AF:

0.118

Gnomad4 OTH exome

AF:

0.111

GnomAD4 genome

AF:

0.0973

AC:

14815

AN:

152312

Hom.:

794

Cov.:

AF XY:

0.0949

AC XY:

7067

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0654

Gnomad4 AMR

AF:

0.0869

Gnomad4 ASJ

AF:

0.137

Gnomad4 EAS

AF:

0.0694

Gnomad4 SAS

AF:

0.118

Gnomad4 FIN

AF:

0.0865

Gnomad4 NFE

AF:

0.117

Gnomad4 OTH

AF:

0.106

Alfa

AF:

0.114

Hom.:

1111

Bravo

AF:

0.0969

Asia WGS

AF:

0.0920

AC:

317

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

WFS1-Related Spectrum Disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

This variant is associated with the following publications: (PMID: 23650218) -

Autosomal dominant nonsyndromic hearing loss 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

Cadd

Benign

4.2

Dann

Benign

0.47

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