rs3812052

Variant names:

• chr5-127457282-T-A
• rs3812052
• NM_001256545.2:c.3387T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-127457282-T-A
• chr5-127457282-T-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001256545.2(MEGF10):​c.3387T>A​(p.Gly1129Gly) 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
• Publications: 19 publications found

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]

MEGF10 Gene-Disease associations (from GenCC):

• MEGF10-related myopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 262076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.3387T>A	p.Gly1129Gly	synonymous_variant	Exon 25 of 25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.3387T>A	p.Gly1129Gly	synonymous_variant	Exon 25 of 25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.3387T>A	p.Gly1129Gly	synonymous_variant	Exon 26 of 26	1		ENSP00000274473.6
MEGF10	ENST00000515622.1	n.433+1675T>A		intron_variant	Intron 4 of 4	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

GnomAD2 exomes AF: 0.528 AC: 132339 AN: 250420 AF XY: 0.538

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 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

African (AFR) AF: 0.214 AC: 7162 AN: 33474

American (AMR) AF: 0.467 AC: 20861 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.608 AC: 15900 AN: 26132

East Asian (EAS) AF: 0.292 AC: 11599 AN: 39690

South Asian (SAS) AF: 0.478 AC: 41173 AN: 86206

European-Finnish (FIN) AF: 0.602 AC: 32060 AN: 53294

Middle Eastern (MID) AF: 0.639 AC: 3684 AN: 5764

European-Non Finnish (NFE) AF: 0.618 AC: 687168 AN: 1111852

Other (OTH) AF: 0.562 AC: 33952 AN: 60376

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

African (AFR) AF: 0.226 AC: 9362 AN: 41432

American (AMR) AF: 0.505 AC: 7715 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 2073 AN: 3470

East Asian (EAS) AF: 0.299 AC: 1540 AN: 5150

South Asian (SAS) AF: 0.446 AC: 2146 AN: 4816

European-Finnish (FIN) AF: 0.602 AC: 6359 AN: 10558

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.622 AC: 42274 AN: 67954

Other (OTH) AF: 0.527 AC: 1114 AN: 2114

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

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

MEGF10-related myopathy Benign:3

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.12
DANN	Benign	0.38
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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