rs143762717
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP6
The NM_001130987.2(DYSF):c.6174G>A(p.Arg2058=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000889 in 1,614,068 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001130987.2 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.6174G>A | p.Arg2058= | splice_region_variant, synonymous_variant | 55/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.6057G>A | p.Arg2019= | splice_region_variant, synonymous_variant | 54/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.6174G>A | p.Arg2058= | splice_region_variant, synonymous_variant | 55/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.6057G>A | p.Arg2019= | splice_region_variant, synonymous_variant | 54/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000460 AC: 70AN: 152064Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000485 AC: 122AN: 251478Hom.: 1 AF XY: 0.000515 AC XY: 70AN XY: 135918
GnomAD4 exome AF: 0.000934 AC: 1365AN: 1461886Hom.: 1 Cov.: 31 AF XY: 0.000903 AC XY: 657AN XY: 727246
GnomAD4 genome ? AF: 0.000460 AC: 70AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.000444 AC XY: 33AN XY: 74402
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 29, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 23, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 12, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 22, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2018 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing;provider interpretation | Kids Neuroscience Centre, Sydney Children's Hospitals Network | - | No evidence that the c.6057G>A variant affects the splicing of DYSF mRNA. This variant is synonymous p.(Arg2019=) and is not predicted to impact the DYSF protein. - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 13, 2020 | - - |
Qualitative or quantitative defects of dysferlin Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 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 | - - |
Miyoshi myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 23, 2023 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
DYSF-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 14, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at