rs141233896
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_006005.3(WFS1):āc.647C>Gā(p.Pro216Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000627 in 1,610,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.00024 ( 0 hom., cov: 33)
Exomes š: 0.000045 ( 0 hom. )
Consequence
WFS1
NM_006005.3 missense
NM_006005.3 missense
Scores
1
4
13
Clinical Significance
Conservation
PhyloP100: 5.97
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 Uncertain_significance. Variant got 0 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.18278906).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.647C>G | p.Pro216Arg | missense_variant | 6/8 | ENST00000226760.5 | |
WFS1 | NM_001145853.1 | c.647C>G | p.Pro216Arg | missense_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.647C>G | p.Pro216Arg | missense_variant | 6/8 | 1 | NM_006005.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000236 AC: 36AN: 152230Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000655 AC: 16AN: 244194Hom.: 0 AF XY: 0.0000528 AC XY: 7AN XY: 132628
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GnomAD4 exome AF: 0.0000446 AC: 65AN: 1458692Hom.: 0 Cov.: 31 AF XY: 0.0000441 AC XY: 32AN XY: 725334
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GnomAD4 genome ? AF: 0.000236 AC: 36AN: 152230Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17AN XY: 74380
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 11, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 15, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 02, 2017 | The p.Pro216Arg variant in WFS1 has not been previously reported in individuals with hearing loss, Wolfram syndrome, or Wolfram-like disorder. This variant has been identified in 0.07% (5/7552) of African chromosomes and 0.02% (10/497210) o f European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs141233896). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic r ole. Computational prediction tools and conservation analysis do not provide str ong support for or against an impact to the protein. In summary, the clinical si gnificance of the p.Pro216Arg variant is uncertain. - |
Monogenic diabetes Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Oct 13, 2015 | ACMG Criteria: PP3, BP4 - |
Wolfram syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy. However no sufficient evidence is found to ascertain the role of this particular variant rs141233896 in Wolfram's syndrome yet. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;B
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at