rs3812054

chr5-127396735-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256545.2(MEGF10):c.616G>A(p.Val206Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,613,958 control chromosomes in the GnomAD database, including 13,248 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (958 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12290 hom.)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.601

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015771091).
• BP6: Variant 5-127396735-G-A is Benign according to our data. Variant chr5-127396735-G-A is described in ClinVar as [Benign]. Clinvar id is 262079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF10	NM_001256545.2	c.616G>A	p.Val206Ile	missense_variant	6/25	ENST00000503335.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF10	ENST00000503335.7	c.616G>A	p.Val206Ile	missense_variant	6/25	1	NM_001256545.2	P1
MEGF10	ENST00000274473.6	c.616G>A	p.Val206Ile	missense_variant	7/26	1		P1
MEGF10	ENST00000418761.6	c.616G>A	p.Val206Ile	missense_variant	7/15	1
MEGF10	ENST00000508365.5	c.616G>A	p.Val206Ile	missense_variant	6/14	1

Frequencies

GnomAD3 genomes AF: 0.108 AC: 16401 AN: 152160 Hom.: 956 Cov.: 32

Gnomad AFR AF: 0.0708

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0830

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0586

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.106

GnomAD3 exomes AF: 0.110 AC: 27684 AN: 250708 Hom.: 1740 AF XY: 0.112 AC XY: 15225 AN XY: 135676

Gnomad AFR exome AF: 0.0679

Gnomad AMR exome AF: 0.0610

Gnomad ASJ exome AF: 0.0968

Gnomad EAS exome AF: 0.0506

Gnomad SAS exome AF: 0.104

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.127 AC: 185530 AN: 1461680 Hom.: 12290 Cov.: 33 AF XY: 0.126 AC XY: 91700 AN XY: 727142

Gnomad4 AFR exome AF: 0.0668

Gnomad4 AMR exome AF: 0.0632

Gnomad4 ASJ exome AF: 0.0900

Gnomad4 EAS exome AF: 0.0719

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.108 AC: 16408 AN: 152278 Hom.: 958 Cov.: 32 AF XY: 0.107 AC XY: 7979 AN XY: 74462

Gnomad4 AFR AF: 0.0707

Gnomad4 AMR AF: 0.0829

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.0585

Gnomad4 SAS AF: 0.117

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.106

Alfa AF: 0.124 Hom.: 3021

Bravo AF: 0.0987

TwinsUK AF: 0.139 AC: 515

ALSPAC AF: 0.134 AC: 516

ESP6500AA AF: 0.0654 AC: 288

ESP6500EA AF: 0.130 AC: 1120

ExAC AF: 0.113 AC: 13766

Asia WGS AF: 0.0770 AC: 269 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.122

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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. -

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 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	1.2
Dann	Benign	0.89
DEOGEN2	Benign	0.015	T;.;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.22	N
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.86	L;L;L;L
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.25	N;N;N;N
REVEL	Benign	0.013
Sift	Benign	0.40	T;T;T;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.0030	B;B;B;B
Vest4		0.042
MPC		0.18
ClinPred		0.00017	T
GERP RS		0.79
Varity_R		0.0097
gMVP		0.052

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: rs3812054; hg19: chr5-126732427; COSMIC: COSV57248712;