rs34997054
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_001130987.2(DYSF):c.386G>A(p.Gly129Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 1,551,712 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0041 ( 9 hom., cov: 33)
Exomes 𝑓: 0.0047 ( 89 hom. )
Consequence
DYSF
NM_001130987.2 missense
NM_001130987.2 missense
Scores
3
9
5
Clinical Significance
Conservation
PhyloP100: 8.15
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 -13 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0076210797).
BP6
?
Variant 2-71511847-G-A is Benign according to our data. Variant chr2-71511847-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94311.We mark this variant Likely_benign, oryginal submissions are: {Benign=10, Likely_benign=3, Likely_pathogenic=1}. Variant chr2-71511847-G-A is described in Lovd as [Likely_benign]. Variant chr2-71511847-G-A is described in Lovd as [Benign]. Variant chr2-71511847-G-A is described in Lovd as [Pathogenic]. Variant chr2-71511847-G-A is described in Lovd as [Pathogenic].
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00468 (6545/1399374) while in subpopulation MID AF= 0.0374 (213/5694). AF 95% confidence interval is 0.0333. There are 89 homozygotes in gnomad4_exome. There are 3348 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 9 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.386G>A | p.Gly129Glu | missense_variant | 5/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.383G>A | p.Gly128Glu | missense_variant | 5/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.386G>A | p.Gly129Glu | missense_variant | 5/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.383G>A | p.Gly128Glu | missense_variant | 5/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00416 AC: 633AN: 152220Hom.: 10 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00713 AC: 1118AN: 156748Hom.: 21 AF XY: 0.00750 AC XY: 619AN XY: 82504
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GnomAD4 exome AF: 0.00468 AC: 6545AN: 1399374Hom.: 89 Cov.: 31 AF XY: 0.00485 AC XY: 3348AN XY: 690198
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GnomAD4 genome ? AF: 0.00414 AC: 631AN: 152338Hom.: 9 Cov.: 33 AF XY: 0.00419 AC XY: 312AN XY: 74494
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ESP6500AA
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ExAC
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Asia WGS
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Benign:17
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 22, 2022 | Variant summary: DYSF c.383G>A (p.Gly128Glu) results in a non-conservative amino acid change located in the Ferlin, first C2 domain (IPR037726) 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 0.0071 in 156748 control chromosomes in the gnomAD database, including 21 homozygotes. The observed variant frequency is approximately 2-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 benign. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and reported the variant with conflicting assessments (benign/likely benign [n=8], uncertain significance [n=2], likely pathogenic [n=1]). Based on the evidence outlined above, the variant was classified as benign. - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 03, 2016 | p.Gly129Glu in exon 5 of DYSF: This variant is not expected to have clinical sig nificance because it has been identified in 1.8% (162/8872) of European chromoso mes, including 3 homozygotes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs34997054). - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 01, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 05, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:4
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Jan 02, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Sep 12, 2017 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | DYSF: BS1, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Muscular dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Jun 18, 2017 | - - |
Autosomal recessive limb-girdle muscular dystrophy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Feb 05, 2024 | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2013 | This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
DYSF-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 16, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Miyoshi muscular dystrophy 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Qualitative or quantitative defects of dysferlin Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D;D;D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;L;L;L;L;.;.;.;.;.;.
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
Uncertain
D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D;D;D;D;D;D
Polyphen
D;D;D;D;D;D;D;D;D;D;D
Vest4
MVP
MPC
0.40
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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