rs10010131

chr4-6291188-A-G

• Frequency:
  • Genomes: 𝑓 0.64 (31429 hom., cov: 31)
  • Exomes 𝑓: 0.66 (55567 hom.)
• Consequence: WFS1 NM_006005 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005842
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:15
• Conservation: PhyloP100: 0.421

ACMG classification

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: GnomAd highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.911 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.461-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000226760.5
WFS1	NM_001145853.1	c.461-9A>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.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

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

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

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:

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, PreventionGenetics	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 17603484, 19330314, 22958899, 22461567) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 07, 2022	- -

Wolfram syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 20, 2020	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. -
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. 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 provided

literature only

OMIM

Aug 01, 2007

- -

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. -

Autosomal dominant nonsyndromic hearing loss 6 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

Cadd

Benign

6.9

Dann

Benign

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000058

dbscSNV1_RF

Benign

0.0

Find out SpliceAI and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10010131; hg19: chr4-6292915;