rs115407852
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BS1
The NM_001130987.2(DYSF):c.6116G>A(p.Arg2039Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,614,206 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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DYSF | ENST00000410020.8 | c.6116G>A | p.Arg2039Gln | missense_variant | Exon 54 of 56 | 1 | NM_001130987.2 | ENSP00000386881.3 | ||
DYSF | ENST00000258104.8 | c.5999G>A | p.Arg2000Gln | missense_variant | Exon 53 of 55 | 1 | NM_003494.4 | ENSP00000258104.3 |
Frequencies
GnomAD3 genomes AF: 0.000223 AC: 34AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000287 AC: 72AN: 251298Hom.: 1 AF XY: 0.000339 AC XY: 46AN XY: 135874
GnomAD4 exome AF: 0.000204 AC: 298AN: 1461872Hom.: 1 Cov.: 32 AF XY: 0.000212 AC XY: 154AN XY: 727234
GnomAD4 genome AF: 0.000223 AC: 34AN: 152334Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74488
ClinVar
Submissions by phenotype
not provided Uncertain:4
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17070050, 11468312, 27884173, 20981092, 20623375) -
PP4 -
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Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:2Benign:1
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Miyoshi muscular dystrophy 1 Uncertain:2
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not specified Uncertain:1Benign:1
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Variant summary: DYSF c.5999G>A (p.Arg2000Gln) results in a conservative amino acid change located in the Ferlin, C-terminal domain (IPR032362) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251298 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (0.00029 vs 0.0031), allowing no conclusion about variant significance. c.5999G>A has been reported in the literature in individuals affected with dysferlinopathy, including Limb-Girdle Muscular Dystrophy and Miyoshi myopathy (Aoki_2001, De Luna_2007, Bardakov_2021, Zhong_2021). Expression of the protein was determined to be absent or reduced in compound heterozygous and carrier individuals (De Luna_2007, De Luna_2012, Bardakov_2021). However, the variant has also been reported in the literature in multiple homozygous unaffected individuals (Boyden_2010, Abouelhoda_2016), while it was found to co-occur in cis with a pathogenic variant (DYSF c.5860G>T, p.Glu1954X) in a compound heterozygous patient. These reports do not provide unequivocal conclusions about association of the variant with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as likely benign and seven ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
DYSF-related disorder Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Primary dilated cardiomyopathy Uncertain:1
Heterozygous variant NM_003494:c.5999G>A (p.Arg2000Gln) in the DYSF gene was found on WES data in female proband (50 y.o., Caucasian) with mitral valve prolapse, mitral insufficiency, cardiomyopathy unspecified. An additional rare candidate variant NM_003737:c.2684C>T (p.Pro895Leu) in the DCHS1 gene (Class III of pathogenicity) was found in this proband. The NM_003494:c.5999G>A variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.0002618 (Date of access 21-04-2023). This variant has been reported in 10 articles in patients with variable phenotypes (PMID: 35047756, 34559919, 33927379, 32906206, 27884173, 22910291, 22194990, 20623375, 17070050, 11468312). Most in silico predictors show benign result of the protein change (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) with following criteria selected: PM2, PP3 -
Qualitative or quantitative defects of dysferlin Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at