rs11950427

Variant names:

• chr5-127433454-T-C
• rs11950427
• NM_001256545.2:c.1785T>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.1785T>C​(p.Pro595Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,632 control chromosomes in the GnomAD database, including 21,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3219 hom., cov: 33)
  • Exomes 𝑓: 0.15 (18255 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.29
• Publications: 9 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=-0.9).
• BP6: Variant 5-127433454-T-C is Benign according to our data. Variant chr5-127433454-T-C is described in ClinVar as Benign. ClinVar VariationId is 262065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.1785T>C	p.Pro595Pro	synonymous_variant	Exon 14 of 25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.1785T>C	p.Pro595Pro	synonymous_variant	Exon 14 of 25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.1785T>C	p.Pro595Pro	synonymous_variant	Exon 15 of 26	1		ENSP00000274473.6
MEGF10	ENST00000506709.1	n.82-1233T>C		intron_variant	Intron 1 of 4	3

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29225 AN: 152046 Hom.: 3213 Cov.: 33

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.139

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.200

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.167

GnomAD2 exomes AF: 0.155 AC: 38860 AN: 250858 AF XY: 0.155

Gnomad AFR exome AF: 0.303

Gnomad AMR exome AF: 0.0824

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.101

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.149

GnomAD4 exome AF: 0.154 AC: 225620 AN: 1461468 Hom.: 18255 Cov.: 32 AF XY: 0.154 AC XY: 112188 AN XY: 726996

African (AFR) AF: 0.302 AC: 10109 AN: 33460

American (AMR) AF: 0.0841 AC: 3759 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 3681 AN: 26102

East Asian (EAS) AF: 0.111 AC: 4395 AN: 39680

South Asian (SAS) AF: 0.174 AC: 15015 AN: 86172

European-Finnish (FIN) AF: 0.190 AC: 10151 AN: 53400

Middle Eastern (MID) AF: 0.119 AC: 686 AN: 5762

European-Non Finnish (NFE) AF: 0.152 AC: 168658 AN: 1111836

Other (OTH) AF: 0.152 AC: 9166 AN: 60368

GnomAD4 genome AF: 0.192 AC: 29260 AN: 152164 Hom.: 3219 Cov.: 33 AF XY: 0.191 AC XY: 14208 AN XY: 74398

African (AFR) AF: 0.301 AC: 12482 AN: 41484

American (AMR) AF: 0.117 AC: 1793 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 539 AN: 3472

East Asian (EAS) AF: 0.108 AC: 559 AN: 5166

South Asian (SAS) AF: 0.200 AC: 964 AN: 4826

European-Finnish (FIN) AF: 0.187 AC: 1986 AN: 10602

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10414 AN: 67990

Other (OTH) AF: 0.166 AC: 352 AN: 2116

Alfa AF: 0.172 Hom.: 1378

Bravo AF: 0.189

Asia WGS AF: 0.143 AC: 501 AN: 3478

EpiCase AF: 0.140

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: 16% 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	-0.90
CADD	Benign	0.0050
DANN	Benign	0.42
PhyloP100		-3.3
Mutation Taster		=99/1	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: rs11950427; hg19: chr5-126769146; COSMIC: COSV57245817;