rs752810646
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_001130987.2(DYSF):c.3190C>T(p.Arg1064Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1064H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.3190C>T | p.Arg1064Cys | missense_variant | 29/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.3136C>T | p.Arg1046Cys | missense_variant | 29/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.3190C>T | p.Arg1064Cys | missense_variant | 29/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.3136C>T | p.Arg1046Cys | missense_variant | 29/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152186Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250506Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135540
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461680Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14AN XY: 727156
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152302Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5AN XY: 74470
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 12, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 04, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24438169) - |
Qualitative or quantitative defects of dysferlin Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1046 of the DYSF protein (p.Arg1046Cys). This variant is present in population databases (rs752810646, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. ClinVar contains an entry for this variant (Variation ID: 447285). 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 DYSF protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1046 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11468312, 18853459, 25591676, 27647186). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 05, 2016 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at