rs140108514
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_001130987.2(DYSF):c.2697+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00042 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000039 ( 0 hom. )
Consequence
DYSF
NM_001130987.2 splice_donor
NM_001130987.2 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.99
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 16 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.020597484 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 2-71568083-G-A is Pathogenic according to our data. Variant chr2-71568083-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 94291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71568083-G-A is described in Lovd as [Pathogenic]. Variant chr2-71568083-G-A is described in Lovd as [Pathogenic]. Variant chr2-71568083-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.2697+1G>A | splice_donor_variant | ENST00000410020.8 | |||
DYSF | NM_003494.4 | c.2643+1G>A | splice_donor_variant | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000258104.8 | c.2643+1G>A | splice_donor_variant | 1 | NM_003494.4 | A1 | |||
DYSF | ENST00000410020.8 | c.2697+1G>A | splice_donor_variant | 1 | NM_001130987.2 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000421 AC: 64AN: 152174Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000115 AC: 29AN: 251492Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135918
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GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461894Hom.: 0 Cov.: 36 AF XY: 0.0000289 AC XY: 21AN XY: 727248
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 23, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 27, 2021 | PM2, PS4_moderate, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 09, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 18, 2022 | This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, including cases of Miyoshi myopathy and limb girdle muscular dystrophy, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. This variant is also referred to as c.2697+1G>A and c.3016+1G>A in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant has been shown to cause exon skipping (PMID: 25312915). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 28, 2022 | Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Published minigene assays show that this canonical splice variant results in the skipping of exon 25, suggesting that it results in abnormal splicing (Kergourlay et al., 2014); This variant is associated with the following publications: (PMID: 22246893, 25525159, 23243261, 12796534, 11532985, 18853459, 29382405, 31980526, 31589614, 33610434, 24438169, 25312915) - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 02, 2014 | - - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The heterozygous c.2697+1G>A variant in DYSF was identified by our study in one individual in the compound heterozygous state, with another pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.1706% (41/24026) of African chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140108514). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The c.2697+1G>A variant in DYSF has been reported in 3 individuals with LGMD (PMID: 23243261). The presence of this variant in combination with reported pathogenic variants and in 2 individuals with LGMD increases the likelihood that the c.2697+1G>A variant is pathogenic. In vitro functional studies provide some evidence that the c.2697+1G>A variant may impact protein function by causing abnormal splicing of Exon 25 (PMID: 25312915). However, these types of assays may not accurately represent biological function.This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an in-frame transcript deletion and abnormal or absent protein. Loss of function In the DYSF gene is an established disease mechanism in autosomal recessive LGMD. In summary, the clinical significance of the 2697+1G>A variant is pathogenic. ACMG/AMP Criteria applied: PVS1_Moderate, PS3, PM3_Strong (Richards 2015). - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Oct 01, 2021 | NM_003494.3(DYSF):c.2643+1G>A is a canonical splice variant classified as pathogenic in the context of dysferlinopathy. c.2643+1G>A has been observed in cases with relevant disease (PMID: 30564623, 12796534, 23243261, 27854218, 18832576, 24488599, 21816046). Functional assessments of this variant are available in the literature (PMID: 25312915). c.2643+1G>A has been observed in population frequency databases (gnomAD: AFR 0.13%). In summary, NM_003494.3(DYSF):c.2643+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Miyoshi muscular dystrophy 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 13, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | research | Center for Genetic Medicine Research, Children's National Medical Center | Dec 01, 2015 | - - |
DYSF-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 26, 2023 | The DYSF c.2643+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous or compound heterozygous state in patients diagnosed with limb-girdle muscular dystrophy type 2B (LGMD2B) or Miyoshi myopathy (Krahn et al. 2009. PubMed ID: 18853459; Takahashi et al. 2013. PubMed ID: 23243261). In a mini-gene assay, the c.2643+1G>A variant led to exon skipping (Kergourlay et al. 2014. PubMed ID: 25312915). This variant has been reported at an allele frequency of ~0.2% in an African population; in other ethnicities it is absent or reported less frequently (i.e. <0.01%) (http://gnomad.broadinstitute.org/variant/2-71795213-G-A). Variants that disrupt the consensus splice donor site in DYSF are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Qualitative or quantitative defects of dysferlin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change affects a donor splice site in intron 25 of the DYSF gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs140108514, gnomAD 0.2%). Disruption of this splice site has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy and Miyoshi myopathy (PMID: 12796534, 18853459, 21816046, 22246893, 23243261, 27854218). This variant is also known as G3016+1A and c.3016+1G>A. ClinVar contains an entry for this variant (Variation ID: 94291). Studies have shown that disruption of this splice site results in skipping of exon 25, but is expected to preserve the integrity of the reading-frame (PMID: 25312915). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
GERP RS
Splicing
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Calibrated prediction
Score
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at