2-71612711-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001130987.2(DYSF):c.4292G>A(p.Arg1431His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1431C) has been classified as Uncertain significance.
Frequency
Consequence
NM_001130987.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DYSF | NM_001130987.2 | c.4292G>A | p.Arg1431His | missense_variant | 39/56 | ENST00000410020.8 | |
DYSF | NM_003494.4 | c.4238G>A | p.Arg1413His | missense_variant | 39/55 | ENST00000258104.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DYSF | ENST00000410020.8 | c.4292G>A | p.Arg1431His | missense_variant | 39/56 | 1 | NM_001130987.2 | A1 | |
DYSF | ENST00000258104.8 | c.4238G>A | p.Arg1413His | missense_variant | 39/55 | 1 | NM_003494.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251358Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135876
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461866Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19AN XY: 727236
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152208Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74360
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2022 | The c.4238G>A (p.R1413H) alteration is located in exon 39 (coding exon 39) of the DYSF gene. This alteration results from a G to A substitution at nucleotide position 4238, causing the arginine (R) at amino acid position 1413 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 09, 2018 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2B Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2020 | - - |
Qualitative or quantitative defects of dysferlin Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 18, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1413 of the DYSF protein (p.Arg1413His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 569799). 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 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at