chr5-127398759-A-G

Position:

• chr5-127398759-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001256545.2(MEGF10):​c.743A>G​(p.His248Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.28

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.743A>G	p.His248Arg	missense_variant	7/25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.743A>G	p.His248Arg	missense_variant	7/25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.743A>G	p.His248Arg	missense_variant	8/26	1		ENSP00000274473.6
MEGF10	ENST00000418761.6	c.743A>G	p.His248Arg	missense_variant	8/15	1		ENSP00000416284.2
MEGF10	ENST00000508365.5	c.743A>G	p.His248Arg	missense_variant	7/14	1		ENSP00000423195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MEGF10-related myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 09, 2019

This sequence change replaces histidine with arginine at codon 248 of the MEGF10 protein (p.His248Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MEGF10-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	.;.;T;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.39	T;T;T;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		1.0	D;B;B;D
Vest4		0.80
MutPred		0.30		Gain of phosphorylation at T250 (P = 0.0784);Gain of phosphorylation at T250 (P = 0.0784);Gain of phosphorylation at T250 (P = 0.0784);Gain of phosphorylation at T250 (P = 0.0784);
MVP		0.27
MPC		0.28
ClinPred		0.81	D
GERP RS		5.8
Varity_R		0.23
gMVP		0.39

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: rs1286512106; hg19: chr5-126734451;