rs115013641
Positions:
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2
The NM_001130987.2(DYSF):c.5743G>A(p.Asp1915Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,614,120 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0027 ( 6 hom., cov: 33)
Exomes 𝑓: 0.0035 ( 27 hom. )
Consequence
DYSF
NM_001130987.2 missense
NM_001130987.2 missense
Scores
8
9
Clinical Significance
Conservation
PhyloP100: 2.78
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 Benign. Variant got -14 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001130987.2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.010743886).
BP6
?
Variant 2-71669705-G-A is Benign according to our data. Variant chr2-71669705-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 94341.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-71669705-G-A is described in Lovd as [Benign]. Variant chr2-71669705-G-A is described in Lovd as [Likely_benign]. Variant chr2-71669705-G-A is described in Lovd as [Pathogenic].
BS2
?
High Homozygotes in GnomAd4 at 6 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.5743G>A | p.Asp1915Asn | missense_variant | 51/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.5626G>A | p.Asp1876Asn | missense_variant | 50/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.5743G>A | p.Asp1915Asn | missense_variant | 51/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.5626G>A | p.Asp1876Asn | missense_variant | 50/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00275 AC: 418AN: 152118Hom.: 6 Cov.: 33
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GnomAD3 exomes AF: 0.00396 AC: 996AN: 251492Hom.: 11 AF XY: 0.00437 AC XY: 594AN XY: 135920
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GnomAD4 exome AF: 0.00355 AC: 5188AN: 1461884Hom.: 27 Cov.: 32 AF XY: 0.00378 AC XY: 2752AN XY: 727242
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GnomAD4 genome ? AF: 0.00273 AC: 416AN: 152236Hom.: 6 Cov.: 33 AF XY: 0.00277 AC XY: 206AN XY: 74432
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:5
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 24, 2018 | This variant is associated with the following publications: (PMID: 25525159, 21522182, 17897828, 22046204, 24838345) - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 09, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | DYSF: BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 22, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 04, 2022 | Variant summary: DYSF c.5626G>A (p.Asp1876Asn) results in a conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.004 in 251492 control chromosomes, predominantly at a frequency of 0.0087 within the South Asian subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=4) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as benign. - |
Qualitative or quantitative defects of dysferlin Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jul 31, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 27, 2022 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 15, 2019 | - - |
Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C5553104:Miyoshi myopathy Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Uncertain significance and reported on 01-23-2012 by Lab or GTR ID 1012. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Benign
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
T;T;T;T;T;T;T;T;T;T;T
Polyphen
B;B;B;B;B;B;B;B;B;B;B
Vest4
MVP
MPC
0.29
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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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