rs113794264

Positions:

• chr5-127396728-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001256545.2(MEGF10):​c.609C>T​(p.Cys203Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,614,048 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0082 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (110 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.830

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 5-127396728-C-T is Benign according to our data. Variant chr5-127396728-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262078.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6}.
• BP7: Synonymous conserved (PhyloP=-0.83 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00821 (1251/152342) while in subpopulation NFE AF= 0.0126 (858/68026). AF 95% confidence interval is 0.0119. There are 7 homozygotes in gnomad4. There are 542 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.609C>T	p.Cys203Cys	synonymous_variant	6/25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.609C>T	p.Cys203Cys	synonymous_variant	6/25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.609C>T	p.Cys203Cys	synonymous_variant	7/26	1		ENSP00000274473.6
MEGF10	ENST00000418761.6	c.609C>T	p.Cys203Cys	synonymous_variant	7/15	1		ENSP00000416284.2
MEGF10	ENST00000508365.5	c.609C>T	p.Cys203Cys	synonymous_variant	6/14	1		ENSP00000423195.1

Frequencies

GnomAD3 genomes AF: 0.00822 AC: 1252 AN: 152224 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.0306

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00583

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00858 AC: 2153 AN: 250822 Hom.: 14 AF XY: 0.00858 AC XY: 1165 AN XY: 135720

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.00654

Gnomad ASJ exome AF: 0.0356

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00605

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00833

GnomAD4 exome AF: 0.0118 AC: 17285 AN: 1461706 Hom.: 110 Cov.: 33 AF XY: 0.0118 AC XY: 8545 AN XY: 727148

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.00646

Gnomad4 ASJ exome AF: 0.0364

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00144

Gnomad4 FIN exome AF: 0.00672

Gnomad4 NFE exome AF: 0.0133

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.00821 AC: 1251 AN: 152342 Hom.: 7 Cov.: 32 AF XY: 0.00728 AC XY: 542 AN XY: 74490

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00614

Gnomad4 ASJ AF: 0.0306

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00583

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.0119 Hom.: 4

Bravo AF: 0.00821

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0135

EpiControl AF: 0.0134

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 29, 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

MEGF10-related myopathy Uncertain:1 Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2024

MEGF10: BP4, BP7, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.3
DANN	Benign	0.60

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: rs113794264; hg19: chr5-126732420;