rs10010131

Variant names:

• chr4-6291188-A-G
• rs10010131
• NM_006005.3:c.461-9A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006005.3(WFS1):​c.461-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.639 in 151,444 control chromosomes in the GnomAD database, including 31,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31471 hom., cov: 31)
  • Exomes 𝑓: 0.62 (285946 hom.)
  • Failed GnomAD Quality Control
• Consequence: WFS1 NM_006005.3 intron
• Scores: Splicing: ADA: 0.00005842
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:17
• Conservation: PhyloP100: 0.421
• Publications: 210 publications found

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 Gene-Disease associations (from GenCC):

• Wolfram-like syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
• Wolfram syndrome

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• autosomal dominant nonsyndromic hearing loss 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• cataract 41

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Wolfram syndrome 1

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• type 2 diabetes mellitus

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-6291188-A-G is Benign according to our data. Variant chr4-6291188-A-G is described in ClinVar as Benign. ClinVar VariationId is 4527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.461-9A>G		intron_variant	Intron 4 of 7	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.461-9A>G		intron_variant	Intron 4 of 7		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.461-9A>G		intron_variant	Intron 4 of 7	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.639 AC: 96669 AN: 151326 Hom.: 31429 Cov.: 31

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.387

Gnomad AMR AF: 0.699

Gnomad ASJ AF: 0.678

Gnomad EAS AF: 0.933

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.654

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.656

GnomAD2 exomes AF: 0.662 AC: 164492 AN: 248508 AF XY: 0.659

Gnomad AFR exome AF: 0.658

Gnomad AMR exome AF: 0.748

Gnomad ASJ exome AF: 0.694

Gnomad EAS exome AF: 0.931

Gnomad FIN exome AF: 0.570

Gnomad NFE exome AF: 0.595

Gnomad OTH exome AF: 0.652

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.622 AC: 906540 AN: 1457304 Hom.: 285946 Cov.: 50 AF XY: 0.624 AC XY: 452378 AN XY: 725028

African (AFR) AF: 0.660 AC: 22060 AN: 33418

American (AMR) AF: 0.744 AC: 33228 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 18098 AN: 26120

East Asian (EAS) AF: 0.959 AC: 38045 AN: 39692

South Asian (SAS) AF: 0.702 AC: 60549 AN: 86228

European-Finnish (FIN) AF: 0.575 AC: 29299 AN: 50922

Middle Eastern (MID) AF: 0.628 AC: 3623 AN: 5766

European-Non Finnish (NFE) AF: 0.597 AC: 662684 AN: 1110158

Other (OTH) AF: 0.646 AC: 38954 AN: 60316

GnomAD4 genome AF: 0.639 AC: 96763 AN: 151444 Hom.: 31471 Cov.: 31 AF XY: 0.641 AC XY: 47452 AN XY: 73980

African (AFR) AF: 0.654 AC: 27009 AN: 41278

American (AMR) AF: 0.700 AC: 10670 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.678 AC: 2349 AN: 3464

East Asian (EAS) AF: 0.934 AC: 4759 AN: 5096

South Asian (SAS) AF: 0.710 AC: 3407 AN: 4796

European-Finnish (FIN) AF: 0.571 AC: 5982 AN: 10478

Middle Eastern (MID) AF: 0.645 AC: 187 AN: 290

European-Non Finnish (NFE) AF: 0.600 AC: 40662 AN: 67782

Other (OTH) AF: 0.660 AC: 1389 AN: 2106

Alfa AF: 0.625 Hom.: 61871

Bravo AF: 0.651

Asia WGS AF: 0.818 AC: 2846 AN: 3478

EpiCase AF: 0.605

EpiControl AF: 0.607

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 04, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17603484, 19330314, 22958899, 22461567) -

Nov 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Wolfram syndrome 1 Benign:2

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. rs10010131 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -

Nov 20, 2020

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Population allele frequency is 66% (rs10010131; 180,328/274,176 alleles in gnomAD v2.0). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria are met: BA1. -

Type 2 diabetes mellitus Pathogenic:1

Mar 06, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

WFS1-Related Spectrum Disorders Benign:1

Jan 12, 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 12, 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. -

Wolfram syndrome Benign:1

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.1
DANN	Benign	0.48
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000058
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs10010131; hg19: chr4-6292915;