rs10519949

Variant names:

• chr5-127331434-T-C
• rs10519949
• NM_001256545.2:c.116+10T>C

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.116+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 1,516,882 control chromosomes in the GnomAD database, including 917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (128 hom., cov: 32)
  • Exomes 𝑓: 0.022 (789 hom.)
• Consequence: MEGF10 NM_001256545.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.716
• Publications: 4 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 (BayesDel_noAF=-0.64).
• BP6: Variant 5-127331434-T-C is Benign according to our data. Variant chr5-127331434-T-C is described in ClinVar as [Benign]. Clinvar id is 262061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.116+10T>C		intron_variant	Intron 2 of 24	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.116+10T>C		intron_variant	Intron 2 of 24	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.116+10T>C		intron_variant	Intron 3 of 25	1		ENSP00000274473.6
MEGF10	ENST00000418761.6	c.116+10T>C		intron_variant	Intron 3 of 14	1		ENSP00000416284.2
MEGF10	ENST00000508365.5	c.116+10T>C		intron_variant	Intron 2 of 13	1		ENSP00000423195.1

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4600 AN: 152130 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.0913

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0333 AC: 8121 AN: 243834 AF XY: 0.0351

Gnomad AFR exome AF: 0.0473

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.0512

Gnomad EAS exome AF: 0.109

Gnomad FIN exome AF: 0.0166

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0216 AC: 29420 AN: 1364634 Hom.: 789 Cov.: 21 AF XY: 0.0233 AC XY: 15932 AN XY: 683978

African (AFR) AF: 0.0510 AC: 1597 AN: 31304

American (AMR) AF: 0.0125 AC: 536 AN: 42964

Ashkenazi Jewish (ASJ) AF: 0.0494 AC: 1246 AN: 25234

East Asian (EAS) AF: 0.112 AC: 4378 AN: 39174

South Asian (SAS) AF: 0.0825 AC: 6794 AN: 82382

European-Finnish (FIN) AF: 0.0165 AC: 879 AN: 53266

Middle Eastern (MID) AF: 0.0346 AC: 193 AN: 5574

European-Non Finnish (NFE) AF: 0.0119 AC: 12220 AN: 1027594

Other (OTH) AF: 0.0276 AC: 1577 AN: 57142

GnomAD4 genome AF: 0.0302 AC: 4605 AN: 152248 Hom.: 128 Cov.: 32 AF XY: 0.0318 AC XY: 2370 AN XY: 74436

African (AFR) AF: 0.0483 AC: 2005 AN: 41540

American (AMR) AF: 0.0151 AC: 231 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 181 AN: 3470

East Asian (EAS) AF: 0.112 AC: 580 AN: 5182

South Asian (SAS) AF: 0.0911 AC: 440 AN: 4828

European-Finnish (FIN) AF: 0.0195 AC: 207 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0126 AC: 855 AN: 68012

Other (OTH) AF: 0.0275 AC: 58 AN: 2112

Alfa AF: 0.0193 Hom.: 62

Bravo AF: 0.0294

Asia WGS AF: 0.0850 AC: 297 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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: 3.5% of total chromosomes in ExAC, 11% of E. Asian chromosomes -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 10, 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	-0.64
CADD	Benign	9.1
DANN	Benign	0.82
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10519949; hg19: chr5-126667126; COSMIC: COSV57246306;