2-71665251-A-T
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001130987.2(DYSF):c.5264A>T(p.Tyr1755Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal recessive limb-girdle muscular dystrophyInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- neuromuscular disease caused by qualitative or quantitative defects of dysferlinInheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
- autosomal recessive limb-girdle muscular dystrophy type 2BInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
- distal myopathy with anterior tibial onsetInheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- congenital myopathy, Paradas typeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Miyoshi myopathyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.5264A>T | p.Tyr1755Phe | missense_variant | Exon 47 of 56 | 1 | NM_001130987.2 | ENSP00000386881.3 | ||
DYSF | ENST00000258104.8 | c.5147A>T | p.Tyr1716Phe | missense_variant | Exon 46 of 55 | 1 | NM_003494.4 | ENSP00000258104.3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.0000239 AC: 6AN: 251466 AF XY: 0.0000441 show subpopulations
GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 727244 show subpopulations
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74356 show subpopulations
ClinVar
Submissions by phenotype
Neuromuscular disease caused by qualitative or quantitative defects of dysferlin Uncertain:2
This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1716 of the DYSF protein (p.Tyr1716Phe). This variant is present in population databases (rs755108809, gnomAD 0.005%). 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: 285750). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DYSF protein function. 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. -
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not provided Uncertain:1
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Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at