rs3812055

Positions:

• chr5-127396707-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256545.2(MEGF10):​c.588G>A​(p.Gln196=) variant causes a synonymous change. The variant allele was found at a frequency of 0.153 in 1,614,004 control chromosomes in the GnomAD database, including 19,387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2235 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17152 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.89

Genes affected

MEGF10 (HGNC:29634): (multiple EGF like domains 10) This gene encodes a member of the multiple epidermal growth factor-like domains protein family. The encoded protein plays a role in cell adhesion, motility and proliferation, and is a critical mediator of apoptotic cell phagocytosis as well as amyloid-beta peptide uptake in the brain. Expression of this gene may be associated with schizophrenia, and mutations in this gene are a cause of early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) as well as congenital myopathy with minicores. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 5-127396707-G-A is Benign according to our data. Variant chr5-127396707-G-A is described in ClinVar as [Benign]. Clinvar id is 262077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.588G>A	p.Gln196=	synonymous_variant	6/25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.588G>A	p.Gln196=	synonymous_variant	6/25	1	NM_001256545.2	ENSP00000423354	P1
MEGF10	ENST00000274473.6	c.588G>A	p.Gln196=	synonymous_variant	7/26	1		ENSP00000274473	P1
MEGF10	ENST00000418761.6	c.588G>A	p.Gln196=	synonymous_variant	7/15	1		ENSP00000416284
MEGF10	ENST00000508365.5	c.588G>A	p.Gln196=	synonymous_variant	6/14	1		ENSP00000423195

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25459 AN: 152134 Hom.: 2228 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.153

GnomAD3 exomes AF: 0.147 AC: 36777 AN: 250994 Hom.: 2931 AF XY: 0.148 AC XY: 20045 AN XY: 135780

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.0823

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.0987

Gnomad SAS exome AF: 0.170

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.151 AC: 220773 AN: 1461752 Hom.: 17152 Cov.: 33 AF XY: 0.151 AC XY: 109609 AN XY: 727178

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.0843

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.168

Gnomad4 FIN exome AF: 0.170

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.145

GnomAD4 genome AF: 0.167 AC: 25491 AN: 152252 Hom.: 2235 Cov.: 32 AF XY: 0.166 AC XY: 12367 AN XY: 74450

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.105

Gnomad4 SAS AF: 0.194

Gnomad4 FIN AF: 0.164

Gnomad4 NFE AF: 0.150

Gnomad4 OTH AF: 0.152

Alfa AF: 0.149 Hom.: 3700

Bravo AF: 0.164

Asia WGS AF: 0.135 AC: 472 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.137

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 15% of total chromosomes in ExAC -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

MEGF10-related myopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.5
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3812055; hg19: chr5-126732399; COSMIC: COSV57248707;