5-127410585-C-T

Variant names:

• chr5-127410585-C-T
• rs31483
• NM_001256545.2:c.1114C>T

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.1114C>T​(p.Leu372Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 1,606,830 control chromosomes in the GnomAD database, including 691,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68318 hom., cov: 34)
  • Exomes 𝑓: 0.93 (622695 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.168
• Publications: 15 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=-0.64).
• BP6: Variant 5-127410585-C-T is Benign according to our data. Variant chr5-127410585-C-T is described in ClinVar as Benign. ClinVar VariationId is 262060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.168 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.978 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.1114C>T	p.Leu372Leu	synonymous_variant	Exon 9 of 25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.1114C>T	p.Leu372Leu	synonymous_variant	Exon 9 of 25	1	NM_001256545.2	ENSP00000423354.2

Frequencies

GnomAD3 genomes AF: 0.946 AC: 144063 AN: 152224 Hom.: 68260 Cov.: 34

Gnomad AFR AF: 0.986

Gnomad AMI AF: 0.934

Gnomad AMR AF: 0.959

Gnomad ASJ AF: 0.958

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.967

Gnomad FIN AF: 0.922

Gnomad MID AF: 0.965

Gnomad NFE AF: 0.917

Gnomad OTH AF: 0.942

GnomAD2 exomes AF: 0.944 AC: 230324 AN: 243864 AF XY: 0.943

Gnomad AFR exome AF: 0.987

Gnomad AMR exome AF: 0.967

Gnomad ASJ exome AF: 0.950

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.925

Gnomad NFE exome AF: 0.920

Gnomad OTH exome AF: 0.938

GnomAD4 exome AF: 0.925 AC: 1345477 AN: 1454488 Hom.: 622695 Cov.: 45 AF XY: 0.926 AC XY: 670213 AN XY: 723514

African (AFR) AF: 0.987 AC: 33001 AN: 33442

American (AMR) AF: 0.966 AC: 43014 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.949 AC: 24779 AN: 26110

East Asian (EAS) AF: 1.00 AC: 39659 AN: 39668

South Asian (SAS) AF: 0.965 AC: 82887 AN: 85882

European-Finnish (FIN) AF: 0.925 AC: 44251 AN: 47834

Middle Eastern (MID) AF: 0.959 AC: 5458 AN: 5690

European-Non Finnish (NFE) AF: 0.914 AC: 1016037 AN: 1111070

Other (OTH) AF: 0.936 AC: 56391 AN: 60256

GnomAD4 genome AF: 0.946 AC: 144180 AN: 152342 Hom.: 68318 Cov.: 34 AF XY: 0.947 AC XY: 70546 AN XY: 74494

African (AFR) AF: 0.986 AC: 41026 AN: 41592

American (AMR) AF: 0.959 AC: 14677 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.958 AC: 3325 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5175 AN: 5176

South Asian (SAS) AF: 0.966 AC: 4668 AN: 4830

European-Finnish (FIN) AF: 0.922 AC: 9800 AN: 10624

Middle Eastern (MID) AF: 0.966 AC: 284 AN: 294

European-Non Finnish (NFE) AF: 0.917 AC: 62380 AN: 68020

Other (OTH) AF: 0.943 AC: 1993 AN: 2114

Alfa AF: 0.931 Hom.: 124238

Bravo AF: 0.952

Asia WGS AF: 0.984 AC: 3421 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 05, 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: 94% of total chromosomes in ExAC -

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PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

MEGF10-related myopathy Benign:3

Sep 05, 2021

Genome-Nilou Lab

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.5
DANN	Benign	0.86
PhyloP100		-0.17
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: rs31483; hg19: chr5-126746277; COSMIC: COSV108037270;