rs753861836
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The ENST00000410020.8(DYSF):c.5785-7G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
ENST00000410020.8 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.5785-7G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000410020.8 | NP_001124459.1 | |||
DYSF | NM_003494.4 | c.5668-7G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000258104.8 | NP_003485.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000258104.8 | c.5668-7G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_003494.4 | ENSP00000258104 | A1 | |||
DYSF | ENST00000410020.8 | c.5785-7G>A | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_001130987.2 | ENSP00000386881 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251410Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135896
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461376Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727034
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74314
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 19, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 28, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jul 21, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 03, 2023 | Non-canonical splice site variant demonstrated to result in loss of function (Kergourlay et al., 2014; Izumi et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16100712, 31589614, 34559919, 32400077, 25312915, 25591676, 33610434, 29794729) - |
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Nov 11, 2021 | This sequence change in DYSF is an intronic variant located in intron 50. The highest population minor allele frequency in gnomAD v2.1 is 0.003% (1/30,614 alleles) in the South Asian population, which is consistent with a recessive condition. This variant has been detected in at least 10 individuals with dysferlinopathy. Of those individuals, two individuals were homozygous and eight were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and one of those were confirmed in trans by parental testing. Almost all of these individuals underwent dysferlin expression analysis on muscle biopsies, and demonstrated deficient expression (PMID: 16100712, 18853459, 19528035, 24488599, 32400077, 33927379). The results from multiple in silico splicing predictors (SpliceAI, MaxEntScan, NNSplice) indicate that this variant may impact splicing by creating a de novo acceptor splice site in intron 50 of DYSF. This prediction is confirmed by RT-PCR and mini-gene assays. The assays demonstrated that the variant impacts splicing by leading to inclusion of 5 bp from intron 50 (r.5667_5668ins5668-5_5668-1, p.Lys1889insTrpfs*56; PMID: 16100712, 25312915, 32400077). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3_Moderate, PM2_Supporting, PP3, PP4. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 11, 2023 | Variant summary: DYSF c.5668-7G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: four predict the variant creates a 3' acceptor site. Additionally, three predict the variant weakens the wild-type 3' acceptor site, and one predicts the variant abolishes the wild-type 3' acceptor site. Several publications report experimental evidence supporting these computational predictions, finding that the variant results in the use of a cryptic 3' acceptor site 5 nucleotides upstream of the wild-type site, leading to a frameshift (p.Lys1889insTrpfsX56; e.g., Cagliani_2005, Kergourlay_2014). The variant allele was found at a frequency of 1.2e-05 in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5668-7G>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Limb-Girdle Muscular Dystrophy (e.g., Cagliani_2005, Charnay_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 16100712, 33927379, 25312915). Eight submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n = 7) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Mar 21, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Miyoshi muscular dystrophy 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Qualitative or quantitative defects of dysferlin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 22, 2023 | This sequence change falls in intron 50 of the DYSF gene. It does not directly change the encoded amino acid sequence of the DYSF protein. This variant is present in population databases (rs753861836, gnomAD 0.003%). This variant has been observed in individual(s) with limb-girdle muscular dystrophy type 2B and Miyoshi muscular dystrophy type 1 (PMID: 16100712, 18853459, 19528035, 24488599). ClinVar contains an entry for this variant (Variation ID: 283474). 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