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rs10010131

Variant summary

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

The NM_006005.3(WFS1):c.461-9A>G variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.00005842
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1B:15

Conservation

PhyloP100: 0.421
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 4527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6291188-A-G is described in Lovd as [Benign]. Variant chr4-6291188-A-G is described in Lovd as [Likely_benign].
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/exons MANE UniProt
WFS1NM_006005.3 linkuse as main transcriptc.461-9A>G splice_polypyrimidine_tract_variant, intron_variant ENST00000226760.5
WFS1NM_001145853.1 linkuse as main transcriptc.461-9A>G splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
WFS1ENST00000226760.5 linkuse as main transcriptc.461-9A>G splice_polypyrimidine_tract_variant, intron_variant 1 NM_006005.3 P2

Frequencies

GnomAD3 genomes
AF:
0.639
AC:
96669
AN:
151326
Hom.:
31429
Cov.:
31
show subpopulations
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
GnomAD3 exomes
AF:
0.662
AC:
164492
AN:
248508
Hom.:
55567
AF XY:
0.659
AC XY:
88703
AN XY:
134542
show subpopulations
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 SAS exome
AF:
0.706
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
show subpopulations
Gnomad4 AFR exome
AF:
0.660
Gnomad4 AMR exome
AF:
0.744
Gnomad4 ASJ exome
AF:
0.693
Gnomad4 EAS exome
AF:
0.959
Gnomad4 SAS exome
AF:
0.702
Gnomad4 FIN exome
AF:
0.575
Gnomad4 NFE exome
AF:
0.597
Gnomad4 OTH exome
AF:
0.646
GnomAD4 genome
AF:
0.639
AC:
96763
AN:
151444
Hom.:
31471
Cov.:
31
AF XY:
0.641
AC XY:
47452
AN XY:
73980
show subpopulations
Gnomad4 AFR
AF:
0.654
Gnomad4 AMR
AF:
0.700
Gnomad4 ASJ
AF:
0.678
Gnomad4 EAS
AF:
0.934
Gnomad4 SAS
AF:
0.710
Gnomad4 FIN
AF:
0.571
Gnomad4 NFE
AF:
0.600
Gnomad4 OTH
AF:
0.660
Alfa
AF:
0.621
Hom.:
34905
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:1Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:8
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Likely benign, no assertion criteria providedclinical testingGenetic 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. -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 28, 2012- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Aug 04, 2014- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This variant is associated with the following publications: (PMID: 17603484, 19330314, 22958899, 22461567) -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Wolfram syndrome 1 Benign:2
Benign, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalNov 20, 2020Population 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. -
Benign, criteria provided, single submitterresearchClinical 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. rs10010131 variant is also seen in patients with Diabetes Mellitus. However, the role of this particular variant is yet to be ascertained. -
Type 2 diabetes mellitus Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 06, 2024- -
WFS1-Related Spectrum Disorders Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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
-0.88
Cadd
Benign
5.1
Dann
Benign
0.48

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs10010131; hg19: chr4-6292915; API