rs17164935

Variant names:

• chr5-127455590-G-A
• rs17164935
• NM_001256545.2:c.3215G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256545.2(MEGF10):​c.3215G>A​(p.Arg1072Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 1,613,490 control chromosomes in the GnomAD database, including 20,250 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1072S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1560 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18690 hom.)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.40
• Publications: 24 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012667179).
• BP6: Variant 5-127455590-G-A is Benign according to our data. Variant chr5-127455590-G-A is described in ClinVar as [Benign]. Clinvar id is 262075.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.3215G>A	p.Arg1072Lys	missense_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.3215G>A	p.Arg1072Lys	missense_variant	Exon 24 of 25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.3215G>A	p.Arg1072Lys	missense_variant	Exon 25 of 26	1		ENSP00000274473.6
MEGF10	ENST00000515622.1	n.416G>A		non_coding_transcript_exon_variant	Exon 4 of 5	2
MEGF10	ENST00000510828.5	n.*28G>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21417 AN: 152038 Hom.: 1556 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.135

GnomAD2 exomes AF: 0.138 AC: 34687 AN: 250580 AF XY: 0.140

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.0776

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.0957

Gnomad FIN exome AF: 0.180

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.158 AC: 230230 AN: 1461334 Hom.: 18690 Cov.: 32 AF XY: 0.157 AC XY: 113846 AN XY: 726972

African (AFR) AF: 0.106 AC: 3544 AN: 33456

American (AMR) AF: 0.0801 AC: 3580 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3035 AN: 26124

East Asian (EAS) AF: 0.109 AC: 4318 AN: 39658

South Asian (SAS) AF: 0.121 AC: 10428 AN: 86236

European-Finnish (FIN) AF: 0.183 AC: 9782 AN: 53400

Middle Eastern (MID) AF: 0.114 AC: 657 AN: 5766

European-Non Finnish (NFE) AF: 0.167 AC: 185991 AN: 1111612

Other (OTH) AF: 0.147 AC: 8895 AN: 60376

GnomAD4 genome AF: 0.141 AC: 21448 AN: 152156 Hom.: 1560 Cov.: 32 AF XY: 0.138 AC XY: 10282 AN XY: 74378

African (AFR) AF: 0.111 AC: 4620 AN: 41504

American (AMR) AF: 0.106 AC: 1626 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 443 AN: 3472

East Asian (EAS) AF: 0.103 AC: 536 AN: 5180

South Asian (SAS) AF: 0.134 AC: 644 AN: 4818

European-Finnish (FIN) AF: 0.174 AC: 1838 AN: 10562

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11314 AN: 68008

Other (OTH) AF: 0.135 AC: 285 AN: 2114

Alfa AF: 0.153 Hom.: 8064

Bravo AF: 0.132

TwinsUK AF: 0.171 AC: 633

ALSPAC AF: 0.166 AC: 641

ESP6500AA AF: 0.106 AC: 465

ESP6500EA AF: 0.163 AC: 1404

ExAC AF: 0.141 AC: 17180

Asia WGS AF: 0.111 AC: 388 AN: 3478

EpiCase AF: 0.152

EpiControl AF: 0.149

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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. -

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	15
DANN	Benign	0.76
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.32	.;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.2	N;N
PhyloP100		3.4
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.25	N;N
REVEL	Benign	0.20
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.022
MPC		0.22
ClinPred		0.0026	T
GERP RS		3.0
Varity_R		0.034
gMVP		0.18
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: rs17164935; hg19: chr5-126791282; COSMIC: COSV57245824; COSMIC: COSV57245824;