rs12654455

chr5-127339177-G-Achr5-127339177-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001256545.2(MEGF10):c.174G>A(p.Thr58=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
MEGF10	NM_001256545.2	c.174G>A	p.Thr58=	synonymous_variant	3/25	ENST00000503335.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF10	ENST00000503335.7	c.174G>A	p.Thr58=	synonymous_variant	3/25	1	NM_001256545.2	P1
MEGF10	ENST00000274473.6	c.174G>A	p.Thr58=	synonymous_variant	4/26	1		P1
MEGF10	ENST00000418761.6	c.174G>A	p.Thr58=	synonymous_variant	4/15	1
MEGF10	ENST00000508365.5	c.174G>A	p.Thr58=	synonymous_variant	3/14	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

GnomAD3 exomes AF: 0.0299 AC: 7505 AN: 250732 Hom.: 277 AF XY: 0.0328 AC XY: 4442 AN XY: 135488

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 SAS exome AF: 0.0834

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

Gnomad4 AFR exome AF: 0.00515

Gnomad4 AMR exome AF: 0.0106

Gnomad4 ASJ exome AF: 0.0486

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.0810

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.0241

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

Gnomad4 AFR AF: 0.00561

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.0522

Gnomad4 EAS AF: 0.113

Gnomad4 SAS AF: 0.0906

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0160 Hom.: 59

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:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -

MEGF10-related myopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 07, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	2.0
Dann	Benign	0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs12654455; hg19: chr5-126674869; COSMIC: COSV57246310;