NM_001256545.2:c.174G>A

Variant names:

• chr5-127339177-G-A
• rs12654455
• NM_001256545.2:c.174G>A

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.174G>A​(p.Thr58Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,612,208 control chromosomes in the GnomAD database, including 832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T58T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (71 hom., cov: 32)
  • Exomes 𝑓: 0.020 (761 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.36
• Publications: 6 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=-0.48).
• BP6: Variant 5-127339177-G-A is Benign according to our data. Variant chr5-127339177-G-A is described in ClinVar as Benign. ClinVar VariationId is 262064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.174G>A	p.Thr58Thr	synonymous_variant	Exon 3 of 25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.174G>A	p.Thr58Thr	synonymous_variant	Exon 3 of 25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.174G>A	p.Thr58Thr	synonymous_variant	Exon 4 of 26	1		ENSP00000274473.6
MEGF10	ENST00000418761.6	c.174G>A	p.Thr58Thr	synonymous_variant	Exon 4 of 15	1		ENSP00000416284.2
MEGF10	ENST00000508365.5	c.174G>A	p.Thr58Thr	synonymous_variant	Exon 3 of 14	1		ENSP00000423195.1

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2761 AN: 151954 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.00565

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.0907

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0299 AC: 7505 AN: 250732 AF XY: 0.0328

Gnomad AFR exome AF: 0.00456

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0498

Gnomad EAS exome AF: 0.107

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.0133

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0196 AC: 28552 AN: 1460136 Hom.: 761 Cov.: 29 AF XY: 0.0215 AC XY: 15596 AN XY: 726378

African (AFR) AF: 0.00515 AC: 172 AN: 33402

American (AMR) AF: 0.0106 AC: 474 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0486 AC: 1267 AN: 26078

East Asian (EAS) AF: 0.111 AC: 4405 AN: 39640

South Asian (SAS) AF: 0.0810 AC: 6979 AN: 86124

European-Finnish (FIN) AF: 0.0165 AC: 880 AN: 53398

Middle Eastern (MID) AF: 0.0304 AC: 175 AN: 5752

European-Non Finnish (NFE) AF: 0.0115 AC: 12745 AN: 1110790

Other (OTH) AF: 0.0241 AC: 1455 AN: 60278

GnomAD4 genome AF: 0.0181 AC: 2755 AN: 152072 Hom.: 71 Cov.: 32 AF XY: 0.0201 AC XY: 1493 AN XY: 74316

African (AFR) AF: 0.00561 AC: 233 AN: 41502

American (AMR) AF: 0.0117 AC: 179 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 181 AN: 3470

East Asian (EAS) AF: 0.113 AC: 582 AN: 5172

South Asian (SAS) AF: 0.0906 AC: 436 AN: 4814

European-Finnish (FIN) AF: 0.0195 AC: 206 AN: 10570

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0125 AC: 851 AN: 67982

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0155 Hom.: 67

Bravo AF: 0.0155

Asia WGS AF: 0.0690 AC: 239 AN: 3478

EpiCase AF: 0.0145

EpiControl AF: 0.0133

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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: 3.1% of total chromosomes in ExAC, 11% of E. Asian chromosomes -

Mar 10, 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. -

Jan 11, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 12, 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	-0.48
CADD	Benign	2.0
DANN	Benign	0.86
PhyloP100		-2.4
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: rs12654455; hg19: chr5-126674869; COSMIC: COSV57246310;