chr4-6291188-A-G
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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
NM_006005.3 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00005842
2
Clinical Significance
Conservation
PhyloP100: 0.421
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 |
---|---|---|---|---|---|---|---|
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: 96669AN: 151326Hom.: 31429 Cov.: 31
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GnomAD3 exomes AF: 0.662 AC: 164492AN: 248508Hom.: 55567 AF XY: 0.659 AC XY: 88703AN XY: 134542
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.622 AC: 906540AN: 1457304Hom.: 285946 Cov.: 50 AF XY: 0.624 AC XY: 452378AN XY: 725028
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Data not reliable, filtered out with message: AS_VQSR
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GnomAD4 genome ? AF: 0.639 AC: 96763AN: 151444Hom.: 31471 Cov.: 31 AF XY: 0.641 AC XY: 47452AN XY: 73980
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ClinVar
Significance: Benign
Submissions summary: Pathogenic:1Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:8
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 | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 28, 2012 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 04, 2014 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 17603484, 19330314, 22958899, 22461567) - |
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 | Mar 06, 2024 | - - |
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:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at