rs1553879021
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_006005.3(WFS1):c.2430C>G(p.Phe810Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 34)
Consequence
WFS1
NM_006005.3 missense
NM_006005.3 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 2.86
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 Likely_pathogenic. Variant got 9 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 10 uncertain in NM_006005.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.963
PP5
Variant 4-6302225-C-G is Pathogenic according to our data. Variant chr4-6302225-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 517479.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_risk_allele=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.2430C>G | p.Phe810Leu | missense_variant | 8/8 | ENST00000226760.5 | |
WFS1 | NM_001145853.1 | c.2430C>G | p.Phe810Leu | missense_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.2430C>G | p.Phe810Leu | missense_variant | 8/8 | 1 | NM_006005.3 | P2 | |
ENST00000661896.1 | n.1337+1690G>C | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Cov.: 99
GnomAD4 exome
Cov.:
99
GnomAD4 genome Cov.: 34
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Wolfram syndrome 1 Pathogenic:1
Likely risk allele, 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 rs1553879021 in Wolfram's syndrome yet. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 13, 2017 | The p.Phe810Leu variant in WFS1 has not been previously reported in individuals with hearing loss or in large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, tho ugh this information is not predictive enough to determine pathogenicity. In sum mary, the clinical significance of the p.Phe810Leu variant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of glycosylation at S808 (P = 0.0053);Gain of glycosylation at S808 (P = 0.0053);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at