rs56157640

Variant names:

• chr5-127455564-G-A
• rs56157640
• NM_001256545.2:c.3189G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-127455564-G-A
• chr5-127455564-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001256545.2(MEGF10):​c.3189G>A​(p.Glu1063Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,614,078 control chromosomes in the GnomAD database, including 602 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (54 hom., cov: 32)
  • Exomes 𝑓: 0.022 (548 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.59
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 5-127455564-G-A is Benign according to our data. Variant chr5-127455564-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 380909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0713 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.3189G>A	p.Glu1063Glu	synonymous_variant	Exon 24 of 25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.3189G>A	p.Glu1063Glu	synonymous_variant	Exon 24 of 25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.3189G>A	p.Glu1063Glu	synonymous_variant	Exon 25 of 26	1		ENSP00000274473.6
MEGF10	ENST00000515622.1	n.390G>A		non_coding_transcript_exon_variant	Exon 4 of 5	2
MEGF10	ENST00000510828.5	n.*2G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2849 AN: 152136 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00674

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0476

Gnomad EAS AF: 0.0500

Gnomad SAS AF: 0.0775

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0266 AC: 6667 AN: 251088 AF XY: 0.0291

Gnomad AFR exome AF: 0.00517

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0466

Gnomad EAS exome AF: 0.0500

Gnomad FIN exome AF: 0.0293

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.0262

GnomAD4 exome AF: 0.0218 AC: 31891 AN: 1461824 Hom.: 548 Cov.: 31 AF XY: 0.0231 AC XY: 16829 AN XY: 727218

African (AFR) AF: 0.00511 AC: 171 AN: 33480

American (AMR) AF: 0.0105 AC: 469 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0454 AC: 1187 AN: 26132

East Asian (EAS) AF: 0.0387 AC: 1537 AN: 39684

South Asian (SAS) AF: 0.0661 AC: 5704 AN: 86254

European-Finnish (FIN) AF: 0.0293 AC: 1567 AN: 53416

Middle Eastern (MID) AF: 0.0260 AC: 150 AN: 5768

European-Non Finnish (NFE) AF: 0.0176 AC: 19582 AN: 1111976

Other (OTH) AF: 0.0252 AC: 1524 AN: 60394

GnomAD4 genome AF: 0.0187 AC: 2846 AN: 152254 Hom.: 54 Cov.: 32 AF XY: 0.0206 AC XY: 1530 AN XY: 74442

African (AFR) AF: 0.00672 AC: 279 AN: 41538

American (AMR) AF: 0.0108 AC: 165 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0476 AC: 165 AN: 3466

East Asian (EAS) AF: 0.0500 AC: 259 AN: 5184

South Asian (SAS) AF: 0.0777 AC: 375 AN: 4824

European-Finnish (FIN) AF: 0.0313 AC: 331 AN: 10592

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0174 AC: 1187 AN: 68028

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0187 Hom.: 18

Bravo AF: 0.0153

Asia WGS AF: 0.0500 AC: 173 AN: 3478

EpiCase AF: 0.0182

EpiControl AF: 0.0156

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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: 2.7% of total chromosomes in ExAC, 6.8% of S. Asian chromosomes

Mar 12, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

MEGF10-related myopathy Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.5
DANN	Benign	0.47
PhyloP100		1.6
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: rs56157640; hg19: chr5-126791256;