rs35297901
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_001130987.2(DYSF):c.2477G>A(p.Arg826Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000931 in 1,614,234 control chromosomes in the GnomAD database, including 2 homozygotes. 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. R826W) has been classified as Uncertain significance.
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.2477G>A | p.Arg826Gln | missense_variant | 24/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.2423G>A | p.Arg808Gln | missense_variant | 24/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.2477G>A | p.Arg826Gln | missense_variant | 24/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.2423G>A | p.Arg808Gln | missense_variant | 24/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.000427 AC: 65AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000386 AC: 97AN: 251448Hom.: 1 AF XY: 0.000464 AC XY: 63AN XY: 135902
GnomAD4 exome AF: 0.000984 AC: 1438AN: 1461890Hom.: 2 Cov.: 32 AF XY: 0.000946 AC XY: 688AN XY: 727248
GnomAD4 genome AF: 0.000427 AC: 65AN: 152344Hom.: 0 Cov.: 33 AF XY: 0.000443 AC XY: 33AN XY: 74482
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 18, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 16, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In addition, in silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Reported previously in the heterozygous state as a variant of uncertain significance in two individuals with limb-girdle muscular dystrophy (Nallamilli et al., 2018); This variant is associated with the following publications: (PMID: 32528171, 30564623) - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Mar 31, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Miyoshi muscular dystrophy 1 (MIM#254130), muscular dystrophy, limb-girdle, autosomal recessive 2 (MIM#253601) and myopathy, distal, with anterior tibial onset (MIM#606768). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 105 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated FerB domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS in individuals with proximal muscle weakness or limb girdle muscular dystrophy, either with an unspecified zygosity or as single hits (PMID: 30564623, 32528171). This variant is also consistently classified as a VUS by diagnostic laboratories in ClinVar. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 01, 2020 | - - |
Qualitative or quantitative defects of dysferlin Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Limb-girdle muscular dystrophy, recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 02, 2022 | - - |
Miyoshi myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at