rs35550094

Positions:

• chr5-127410455-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001256545.2(MEGF10):​c.984C>T​(p.Asn328Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00442 in 1,614,190 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (51 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.729

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 5-127410455-C-T is Benign according to our data. Variant chr5-127410455-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 262081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.729 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.984C>T	p.Asn328Asn	synonymous_variant	9/25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.984C>T	p.Asn328Asn	synonymous_variant	9/25	1	NM_001256545.2	ENSP00000423354.2

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2302 AN: 152208 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00579 AC: 1456 AN: 251420 Hom.: 19 AF XY: 0.00497 AC XY: 675 AN XY: 135876

Gnomad AFR exome AF: 0.0495

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00331 AC: 4836 AN: 1461864 Hom.: 51 Cov.: 31 AF XY: 0.00320 AC XY: 2328 AN XY: 727228

Gnomad4 AFR exome AF: 0.0528

Gnomad4 AMR exome AF: 0.00380

Gnomad4 ASJ exome AF: 0.0229

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.00158

Gnomad4 OTH exome AF: 0.00649

GnomAD4 genome AF: 0.0151 AC: 2306 AN: 152326 Hom.: 41 Cov.: 33 AF XY: 0.0151 AC XY: 1127 AN XY: 74488

Gnomad4 AFR AF: 0.0474

Gnomad4 AMR AF: 0.00601

Gnomad4 ASJ AF: 0.0219

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00957 Hom.: 12

Bravo AF: 0.0173

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00450

ClinVar

Significance: Benign/Likely 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	Athena Diagnostics	Dec 30, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 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

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.062
DANN	Benign	0.89

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: rs35550094; hg19: chr5-126746147;