rs759982570
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1_Very_StrongPM1PM2PM5PP5_Very_Strong
The NM_058246.4(DNAJB6):c.273C>G(p.Phe91Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F91V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_058246.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAJB6 | NM_058246.4 | c.273C>G | p.Phe91Leu | missense_variant | 5/10 | ENST00000262177.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAJB6 | ENST00000262177.9 | c.273C>G | p.Phe91Leu | missense_variant | 5/10 | 1 | NM_058246.4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 29
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 16, 2023 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 91 of the DNAJB6 protein (p.Phe91Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 26205529, 26338452, 26371419). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225176). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNAJB6 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects DNAJB6 function (PMID: 26338452, 26371419). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 27, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Neuromuscular Department, Shariati Hospital, Tehran University of Medical Sciences | Oct 01, 2020 | 34-year-old male, with proximal weakness since age of 15 years. He had also distal weakness mostly in hands. Muscle biopsy revealed rimmed vacuoles, and core bodies. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 08, 2016 | - - |
Abnormality of the musculature Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at