rs876657735
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP5BP3
The NM_006005.3(WFS1):c.1060_1062del(p.Phe354del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000192 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S353S) has been classified as Likely benign.
Frequency
Consequence
NM_006005.3 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WFS1 | NM_006005.3 | c.1060_1062del | p.Phe354del | inframe_deletion | 8/8 | ENST00000226760.5 | |
WFS1 | NM_001145853.1 | c.1060_1062del | p.Phe354del | inframe_deletion | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WFS1 | ENST00000226760.5 | c.1060_1062del | p.Phe354del | inframe_deletion | 8/8 | 1 | NM_006005.3 | P2 | |
ENST00000661896.1 | n.1337+3059_1337+3061del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251438Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135892
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461876Hom.: 0 AF XY: 0.0000234 AC XY: 17AN XY: 727244
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74436
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This variant, c.1060_1062del, results in the deletion of 1 amino acid(s) of the WFS1 protein (p.Phe354del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs752154032, gnomAD 0.006%). This variant has been observed in individual(s) with autosomal recessive Wolfram syndrome (PMID: 10521293, 17568405, 22238590). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 228420). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 21, 2016 | - - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 27, 2016 | The p.Phe354del variant in WFS1 has been previously reported in at least 5 proba nds with Wolfram syndrome, 3 of whom were compound heterozygous with a truncatin g variant on the remaining copy of WFS1 (Aloi 2012, Chaussenot 2015, Gasparin 20 09, Gomez-Zaera 2001, Hardy 1999). This variant was absent from large populatio n studies. The variant is an in-frame deletion of three nucleotides that result s in the deletion of a phenylalanine (Phe) at position 354. In summary, this var iant meets our criteria to be classified as pathogenic for autosomal recessive W olfram syndrome based on the previous reports. - |
Monogenic diabetes Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Personalized Diabetes Medicine Program, University of Maryland School of Medicine | Jan 09, 2018 | ACMG criteria: PM4 (nonframeshift), PS4(mod) [Aloi 2012 PMID:22238590 (in trans with nonsense variant), Chaussenot 2015 PMID:24890733 (cmpd het with missense), Gasparin 2009, Gomez-Zaera 2001, Hardy 1999 PMID:10521293), PP5 (Emory) = VUS for Monogenic diabetes. For WFS, ACMG criteria: PM2 (few in database for AR disorder, 3 copies in ExAC), PM4 (nonframeshift), PS4 [Aloi 2012 PMID:22238590 (in trans with nonsense variant), Chaussenot 2015 PMID:24890733 (cmpd het with missense), Gasparin 2009, Gomez-Zaera 2001, Hardy 1999 PMID:10521293), PP5 (Emory); PM3 (in trans with pathogenic variant (PVS1, PM2, PP3 = Pathogenic), PMID:22238590)=pathogenic for WFS/carrier status. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at