rs398123796
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001130987.2(DYSF):βc.5815_5816delβ(p.Ser1939GlnfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000039 ( 0 hom., cov: 33)
Exomes π: 0.00012 ( 0 hom. )
Consequence
DYSF
NM_001130987.2 frameshift
NM_001130987.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
DYSF (HGNC:3097): (dysferlin) The protein encoded by this gene belongs to the ferlin family and is a skeletal muscle protein found associated with the sarcolemma. It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. In addition, the protein encoded by this gene binds caveolin-3, a skeletal muscle membrane protein which is important in the formation of caveolae. Specific mutations in this gene have been shown to cause autosomal recessive limb girdle muscular dystrophy type 2B (LGMD2B) as well as Miyoshi myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 2-71674223-TGA-T is Pathogenic according to our data. Variant chr2-71674223-TGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 94344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71674223-TGA-T is described in Lovd as [Pathogenic]. Variant chr2-71674223-TGA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.5815_5816del | p.Ser1939GlnfsTer14 | frameshift_variant | 52/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.5698_5699del | p.Ser1900GlnfsTer14 | frameshift_variant | 51/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000258104.8 | c.5698_5699del | p.Ser1900GlnfsTer14 | frameshift_variant | 51/55 | 1 | NM_003494.4 | A1 | |
DYSF | ENST00000410020.8 | c.5815_5816del | p.Ser1939GlnfsTer14 | frameshift_variant | 52/56 | 1 | NM_001130987.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152212Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251484Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135920
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GnomAD4 exome AF: 0.000122 AC: 179AN: 1461888Hom.: 0 AF XY: 0.000128 AC XY: 93AN XY: 727244
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GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74354
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 28, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 06, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 22, 2023 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in individuals with limb-girdle muscular dystrophy or Miyoshi muscular dystrophy. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 12, 2018 | The c.5698_5699delAG pathogenic variant in the DYSF gene has been reported previously in multiple unrelated individuals with dysferlinopathy who had a second DYSF variant identified (Takahashi et al., 2003; Klinge et al., 2010; Ankala et al., 2014). Due to use of alternative nomenclature, this variant has also been reported as c.6071_6072delAG (Takahashi et al., 2003). The deletion causes a frameshift starting with codon Serine 1900, changes this amino acid to a Glutamine residue and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Ser1900GlnfsX14. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.5698_5699delAG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2018 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing;provider interpretation | Kids Neuroscience Centre, Sydney Children's Hospitals Network | - | The c.5698_5699del variant creates a frameshift and premature termination codon (p.(Ser1900Glnfs*14)). These transcripts are predicted to be degraded by nonsense mediated decay (NMD). Any mis -spliced DYSF transcripts that escape NMD encode DYSF protein lacking 181 amino acids from the C-terminus, including 42 amino acids from the C2 calcium dependant membrane targeting domain and the entire transmembrane domain. - |
Miyoshi muscular dystrophy 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
Qualitative or quantitative defects of dysferlin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change creates a premature translational stop signal (p.Ser1900Glnfs*14) in the DYSF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (rs778260292, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with Miyoshi myopathy (PMID: 9731526, 18853459, 19528035, 19594366, 23530687). This variant is also known as 6071,2delAG. ClinVar contains an entry for this variant (Variation ID: 94344). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at