rs10519949

chr5-127331434-T-C

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.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

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 (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. Variant chr5-127331434-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
MEGF10	NM_001256545.2	c.116+10T>C		intron_variant		ENST00000503335.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF10	ENST00000503335.7	c.116+10T>C		intron_variant		1	NM_001256545.2	P1
MEGF10	ENST00000274473.6	c.116+10T>C		intron_variant		1		P1
MEGF10	ENST00000418761.6	c.116+10T>C		intron_variant		1
MEGF10	ENST00000508365.5	c.116+10T>C		intron_variant		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

GnomAD3 exomes AF: 0.0333 AC: 8121 AN: 243834 Hom.: 300 AF XY: 0.0351 AC XY: 4621 AN XY: 131652

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 SAS exome AF: 0.0861

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

Gnomad4 AFR exome AF: 0.0510

Gnomad4 AMR exome AF: 0.0125

Gnomad4 ASJ exome AF: 0.0494

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.0825

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.0119

Gnomad4 OTH exome AF: 0.0276

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

Gnomad4 AFR AF: 0.0483

Gnomad4 AMR AF: 0.0151

Gnomad4 ASJ AF: 0.0522

Gnomad4 EAS AF: 0.112

Gnomad4 SAS AF: 0.0911

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0185 Hom.: 46

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

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

MEGF10-related myopathy Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	9.1
Dann	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs10519949; hg19: chr5-126667126; COSMIC: COSV57246306;