rs3812055

Variant names:

• chr5-127396707-G-A
• rs3812055
• NM_001256545.2:c.588G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256545.2(MEGF10):​c.588G>A​(p.Gln196Gln) 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
• Publications: 11 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 -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 VariationId 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 rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.588G>A	p.Gln196Gln	synonymous_variant	Exon 6 of 25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.588G>A	p.Gln196Gln	synonymous_variant	Exon 6 of 25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.588G>A	p.Gln196Gln	synonymous_variant	Exon 7 of 26	1		ENSP00000274473.6
MEGF10	ENST00000418761.6	c.588G>A	p.Gln196Gln	synonymous_variant	Exon 7 of 15	1		ENSP00000416284.2
MEGF10	ENST00000508365.5	c.588G>A	p.Gln196Gln	synonymous_variant	Exon 6 of 14	1		ENSP00000423195.1

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

GnomAD2 exomes AF: 0.147 AC: 36777 AN: 250994 AF XY: 0.148

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 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

African (AFR) AF: 0.227 AC: 7588 AN: 33480

American (AMR) AF: 0.0843 AC: 3768 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3592 AN: 26136

East Asian (EAS) AF: 0.110 AC: 4356 AN: 39700

South Asian (SAS) AF: 0.168 AC: 14459 AN: 86258

European-Finnish (FIN) AF: 0.170 AC: 9040 AN: 53300

Middle Eastern (MID) AF: 0.0997 AC: 575 AN: 5768

European-Non Finnish (NFE) AF: 0.152 AC: 168628 AN: 1111992

Other (OTH) AF: 0.145 AC: 8767 AN: 60394

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

African (AFR) AF: 0.227 AC: 9414 AN: 41536

American (AMR) AF: 0.112 AC: 1709 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 531 AN: 3470

East Asian (EAS) AF: 0.105 AC: 543 AN: 5172

South Asian (SAS) AF: 0.194 AC: 934 AN: 4818

European-Finnish (FIN) AF: 0.164 AC: 1739 AN: 10622

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10203 AN: 68008

Other (OTH) AF: 0.152 AC: 322 AN: 2116

Alfa AF: 0.153 Hom.: 7598

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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: 15% of total chromosomes in ExAC -

Jan 29, 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. -

MEGF10-related myopathy Benign:2

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	-0.47
CADD	Benign	8.5
DANN	Benign	0.83
PhyloP100		5.9
Mutation Taster		=53/47	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: rs3812055; hg19: chr5-126732399; COSMIC: COSV57248707;