rs34211915
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1
This summary comes from the ClinGen Evidence Repository: The NM_003494.4: c.3065G>A variant in DYSF, which is also known as NM_001130987.2: c.3119G>A p.(Arg1040Gln), is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 1022 (p.Arg1022Gln). The filtering allele frequency of the variant is 0.03338 for African/African American genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 3745/152196), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.02, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.39, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA147743/MONDO:0015152/180
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 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.3119G>A | p.Arg1040Gln | missense_variant | Exon 29 of 56 | 1 | NM_001130987.2 | ENSP00000386881.3 | ||
DYSF | ENST00000258104.8 | c.3065G>A | p.Arg1022Gln | missense_variant | Exon 29 of 55 | 1 | NM_003494.4 | ENSP00000258104.3 |
Frequencies
GnomAD3 genomes AF: 0.0246 AC: 3745AN: 152196Hom.: 57 Cov.: 33
GnomAD3 exomes AF: 0.0184 AC: 4611AN: 250548Hom.: 54 AF XY: 0.0177 AC XY: 2404AN XY: 135574
GnomAD4 exome AF: 0.0209 AC: 30594AN: 1461746Hom.: 389 Cov.: 33 AF XY: 0.0200 AC XY: 14576AN XY: 727176
GnomAD4 genome AF: 0.0246 AC: 3746AN: 152310Hom.: 57 Cov.: 33 AF XY: 0.0245 AC XY: 1826AN XY: 74472
ClinVar
Submissions by phenotype
not specified Benign:6
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Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided Benign:5
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DYSF: PM5, BP4, BS1, BS2 -
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Qualitative or quantitative defects of dysferlin Benign:2
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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Autosomal recessive limb-girdle muscular dystrophy Benign:1
The NM_003494.4: c.3065G>A variant in DYSF, which is also known as NM_001130987.2: c.3119G>A p.(Arg1040Gln), is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 1022 (p.Arg1022Gln). The filtering allele frequency of the variant is 0.03338 for African/African American genome chromosomes in gnomAD v3.1.2 (the lower threshold of the 95% CI of 3745/152196), which is higher than the VCEP threshold of 0.003 (BA1). The SpliceAI score for this variant is 0.02, suggesting it does not impact splicing. However, the computational predictor REVEL gives a score of 0.39, which is above the LGMD VCEP threshold predicting a benign impact on DYSF function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): BA1. -
Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at