rs146064054
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_001130987.2(DYSF):c.1449G>A(p.Met483Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000297 in 1,614,124 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 1 hom. )
Consequence
DYSF
NM_001130987.2 missense, splice_region
NM_001130987.2 missense, splice_region
Scores
1
8
10
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.54
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 Uncertain_significance. Variant got 4 ACMG points.
PM1
In a domain C2 3 (size 136) in uniprot entity DYSF_HUMAN there are 42 pathogenic changes around while only 4 benign (91%) in NM_001130987.2
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.1449G>A | p.Met483Ile | missense_variant, splice_region_variant | 15/56 | ENST00000410020.8 | NP_001124459.1 | |
DYSF | NM_003494.4 | c.1353G>A | p.Met451Ile | missense_variant, splice_region_variant | 14/55 | ENST00000258104.8 | NP_003485.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.1449G>A | p.Met483Ile | missense_variant, splice_region_variant | 15/56 | 1 | NM_001130987.2 | ENSP00000386881.3 | ||
DYSF | ENST00000258104.8 | c.1353G>A | p.Met451Ile | missense_variant, splice_region_variant | 14/55 | 1 | NM_003494.4 | ENSP00000258104.3 |
Frequencies
GnomAD3 genomes AF: 0.000177 AC: 27AN: 152134Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251456Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135916
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GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461872Hom.: 1 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727238
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GnomAD4 genome AF: 0.000177 AC: 27AN: 152252Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74454
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2017 | The c.1353 G>A variant in the DYSF gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1353 G>A variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. In-silico splice prediction models predict that c.1353 G>A may damage or destroy the splice donor site in exon 14. However, in the absence of RNA/functional studies, the actual effect of c.1353 G>A change in this individual is unknown. If c.1353 G>A does not alter splicing, it will result in the M451I missense change. The M451I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.1353 G>A as a variant of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 30, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 21, 2020 | - - |
Peripheral neuropathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Claritas Genomics | Aug 22, 2016 | - - |
Distal myopathy with anterior tibial onset;C1850889:Autosomal recessive limb-girdle muscular dystrophy type 2B;C4551973:Miyoshi muscular dystrophy 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 23, 2021 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 23, 2020 | - - |
Qualitative or quantitative defects of dysferlin Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 26, 2022 | This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 451 of the DYSF protein (p.Met451Ile). This variant also falls at the last nucleotide of exon 14, which is part of the consensus splice site for this exon. This variant is present in population databases (rs146064054, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with DYSF-related conditions. ClinVar contains an entry for this variant (Variation ID: 288879). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;.;D;.;.;.;.;.;.
Eigen
Benign
Eigen_PC
Uncertain
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
Benign
T
MutationAssessor
Benign
.;.;L;.;L;.;.;.;.;.;.
PrimateAI
Benign
T
PROVEAN
Uncertain
N;D;N;D;N;D;N;N;N;D;N
REVEL
Benign
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
B;B;B;B;B;B;B;B;B;B;B
Vest4
MutPred
0.66
.;.;Gain of catalytic residue at P453 (P = 0.0363);.;Gain of catalytic residue at P453 (P = 0.0363);.;.;.;.;.;.;
MVP
MPC
0.19
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at