chr5-127455545-G-A
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting
The NM_001256545.2(MEGF10):c.3170G>A(p.Arg1057Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000291 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001256545.2 missense
Scores
Clinical Significance
Conservation
Publications
- MEGF10-related myopathyInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MEGF10 | ENST00000503335.7 | c.3170G>A | p.Arg1057Lys | missense_variant | Exon 24 of 25 | 1 | NM_001256545.2 | ENSP00000423354.2 | ||
MEGF10 | ENST00000274473.6 | c.3170G>A | p.Arg1057Lys | missense_variant | Exon 25 of 26 | 1 | ENSP00000274473.6 | |||
MEGF10 | ENST00000510828.5 | n.669G>A | non_coding_transcript_exon_variant | Exon 6 of 6 | 5 | |||||
MEGF10 | ENST00000515622.1 | n.371G>A | non_coding_transcript_exon_variant | Exon 4 of 5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152138Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000358 AC: 9AN: 251168 AF XY: 0.0000295 show subpopulations
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461834Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15AN XY: 727214 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000131 AC: 20AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74314 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.3170G>A (p.R1057K) alteration is located in exon 25 (coding exon 23) of the MEGF10 gene. This alteration results from a G to A substitution at nucleotide position 3170, causing the arginine (R) at amino acid position 1057 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
MEGF10-related myopathy Uncertain:1
This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 1057 of the MEGF10 protein (p.Arg1057Lys). This variant is present in population databases (rs374156507, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MEGF10-related conditions. ClinVar contains an entry for this variant (Variation ID: 430134). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -
not provided Uncertain:1
A variant of uncertain significance has been identified in the MEGF10 gene. The R1057K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1057K variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1057K 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 where amino acids with similar properties to Arginine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at