rs76086153
Positions:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001130987.2(DYSF):āc.4694A>Cā(p.Lys1565Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000929 in 1,614,200 control chromosomes in the GnomAD database, including 1 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: š 0.00057 ( 0 hom., cov: 32)
Exomes š: 0.000043 ( 1 hom. )
Consequence
DYSF
NM_001130987.2 missense
NM_001130987.2 missense
Scores
2
8
7
Clinical Significance
Conservation
PhyloP100: 6.00
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 Likely_benign. Variant got -2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.047477454).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.4694A>C | p.Lys1565Thr | missense_variant | 43/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.4577A>C | p.Lys1526Thr | missense_variant | 42/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.4694A>C | p.Lys1565Thr | missense_variant | 43/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.4577A>C | p.Lys1526Thr | missense_variant | 42/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000572 AC: 87AN: 152188Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000123 AC: 31AN: 251488Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135916
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GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461894Hom.: 1 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 727248
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GnomAD4 genome ? AF: 0.000571 AC: 87AN: 152306Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46AN XY: 74474
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 02, 2014 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 21, 2015 | - - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 29, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 29, 2019 | This variant is associated with the following publications: (PMID: 20981092, 20544924, 22995991, 18853459) - |
DYSF-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 28, 2023 | The DYSF c.4577A>C variant is predicted to result in the amino acid substitution p.Lys1526Thr. This variant was reported in the homozygous state in one patient with limb-girdle muscular dystrophy who was also found to be homozygous for the c.2643+1G>A splice variant (Krahn et al. 2009. PubMed ID: 18853459). At PreventionGenetics, we have seen the c.4577A>C variant in four other patients; however, three of these patients also carried the c.2643+1G>A variant in the same zygosity (i.e., heterozygous or homozygous) as the c.4577A>C variant. Furthermore, the c.4577A>C variant is present at a similar allele frequency (~0.2%) in the African population in the gnomAD database as the c.2643+1G>A variant (http://gnomad.broadinstitute.org/variant/2-71883359-A-C). Taken together, this evidence suggests the c.4577A>C and c.2643+1G>A variants may commonly reside on the same allele. It is not clear if the c.4577A>C contributes to the phenotype observed in these individuals; therefore, the clinical significance of the c.4577A>C variant is uncertain. - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Qualitative or quantitative defects of dysferlin Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
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
Pathogenic
Sift
Benign
T;T;T;T;T;T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T;T;T;T
Polyphen
P;B;B;D;D;D;D;P;D;D;P
Vest4
MVP
MPC
0.19
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