rs142221815
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_001256545.2(MEGF10):c.669T>A(p.Asp223Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MEGF10 | NM_001256545.2 | c.669T>A | p.Asp223Glu | missense_variant | 7/25 | ENST00000503335.7 | NP_001243474.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MEGF10 | ENST00000503335.7 | c.669T>A | p.Asp223Glu | missense_variant | 7/25 | 1 | NM_001256545.2 | ENSP00000423354 | P1 | |
MEGF10 | ENST00000274473.6 | c.669T>A | p.Asp223Glu | missense_variant | 8/26 | 1 | ENSP00000274473 | P1 | ||
MEGF10 | ENST00000418761.6 | c.669T>A | p.Asp223Glu | missense_variant | 8/15 | 1 | ENSP00000416284 | |||
MEGF10 | ENST00000508365.5 | c.669T>A | p.Asp223Glu | missense_variant | 7/14 | 1 | ENSP00000423195 |
Frequencies
GnomAD3 genomes AF: 0.000355 AC: 54AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000955 AC: 24AN: 251424Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135888
GnomAD4 exome AF: 0.0000349 AC: 51AN: 1461782Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 727192
GnomAD4 genome AF: 0.000355 AC: 54AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74356
ClinVar
Submissions by phenotype
MEGF10-related myopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 05, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 223 of the MEGF10 protein (p.Asp223Glu). This variant is present in population databases (rs142221815, gnomAD 0.1%). 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: 350641). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 26, 2019 | - - |
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 09, 2021 | The c.669T>A (p.D223E) alteration is located in exon 8 (coding exon 6) of the MEGF10 gene. This alteration results from a T to A substitution at nucleotide position 669, causing the aspartic acid (D) at amino acid position 223 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at