rs3812052

chr5-127457282-T-Achr5-127457282-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001256545.2(MEGF10):c.3387T>A(p.Gly1129=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,613,440 control chromosomes in the GnomAD database, including 275,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (20146 hom., cov: 32)
  • Exomes 𝑓: 0.58 (255403 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.65

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 5-127457282-T-A is Benign according to our data. Variant chr5-127457282-T-A is described in ClinVar as [Benign]. Clinvar id is 262076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-127457282-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF10	NM_001256545.2	c.3387T>A	p.Gly1129=	synonymous_variant	25/25	ENST00000503335.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF10	ENST00000503335.7	c.3387T>A	p.Gly1129=	synonymous_variant	25/25	1	NM_001256545.2	P1
MEGF10	ENST00000274473.6	c.3387T>A	p.Gly1129=	synonymous_variant	26/26	1		P1
MEGF10	ENST00000515622.1	n.433+1675T>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.484 AC: 73459 AN: 151854 Hom.: 20144 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.754

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.597

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.523

GnomAD3 exomes AF: 0.528 AC: 132339 AN: 250420 Hom.: 37206 AF XY: 0.538 AC XY: 72844 AN XY: 135276

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.461

Gnomad ASJ exome AF: 0.601

Gnomad EAS exome AF: 0.294

Gnomad SAS exome AF: 0.471

Gnomad FIN exome AF: 0.601

Gnomad NFE exome AF: 0.624

Gnomad OTH exome AF: 0.574

GnomAD4 exome AF: 0.584 AC: 853559 AN: 1461468 Hom.: 255403 Cov.: 57 AF XY: 0.584 AC XY: 424335 AN XY: 727024

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.467

Gnomad4 ASJ exome AF: 0.608

Gnomad4 EAS exome AF: 0.292

Gnomad4 SAS exome AF: 0.478

Gnomad4 FIN exome AF: 0.602

Gnomad4 NFE exome AF: 0.618

Gnomad4 OTH exome AF: 0.562

GnomAD4 genome AF: 0.483 AC: 73466 AN: 151972 Hom.: 20146 Cov.: 32 AF XY: 0.483 AC XY: 35869 AN XY: 74292

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.505

Gnomad4 ASJ AF: 0.597

Gnomad4 EAS AF: 0.299

Gnomad4 SAS AF: 0.446

Gnomad4 FIN AF: 0.602

Gnomad4 NFE AF: 0.622

Gnomad4 OTH AF: 0.527

Alfa AF: 0.585 Hom.: 8609

Bravo AF: 0.466

Asia WGS AF: 0.398 AC: 1383 AN: 3478

EpiCase AF: 0.633

EpiControl AF: 0.641

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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: 53% of total chromosomes in ExAC -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

MEGF10-related myopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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	Genome-Nilou Lab	Sep 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.12
Dann	Benign	0.38

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: rs3812052; hg19: chr5-126792974; COSMIC: COSV57245128; COSMIC: COSV57245128;