rs199954546
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_001130987.2(DYSF):c.2864+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001130987.2 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.2864+1G>A | splice_donor_variant | ENST00000410020.8 | |||
DYSF | NM_003494.4 | c.2810+1G>A | splice_donor_variant | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000258104.8 | c.2810+1G>A | splice_donor_variant | 1 | NM_003494.4 | A1 | |||
DYSF | ENST00000410020.8 | c.2864+1G>A | splice_donor_variant | 1 | NM_001130987.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 249900Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135196
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461630Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4AN XY: 727100
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152276Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74458
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Oct 11, 2017 | ACMG: +PVS1 +PM2 +PP3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 22, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
Miyoshi muscular dystrophy 1 Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Neuromuscular Department, Shariati Hospital, Tehran University of Medical Sciences | Oct 23, 2020 | Since age of 15, the patient developed bilateral foot plantar flexion weakness, difficulty climbing upstairs and some wasting of calf muscles. CK had been elevated and the EMG was myopathic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 06, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2022 | Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in an individual with Miyoshi myopathy in published literature who also harbored a second DYSF variant in trans (Chakravorty et al., 2021); This variant is associated with the following publications: (PMID: 27602406, 31589614, 33610434, 33726816, 26000923, 22213072, Chakravorty2021[Preprint], 18853459) - |
Qualitative or quantitative defects of dysferlin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2023 | This sequence change affects a donor splice site in intron 26 of the DYSF gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DYSF are known to be pathogenic (PMID: 17698709, 20301480). This variant is present in population databases (rs199954546, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with dysferlinopathy (PMID: 17994539, 18853459, 26000923). This variant is also known as IVS26+1G>A. ClinVar contains an entry for this variant (Variation ID: 443997). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at