5-127331311-G-T

Variant names:

• chr5-127331311-G-T
• NM_001256545.2:c.3G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001256545.2(MEGF10):​c.3G>T​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEGF10 NM_001256545.2 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.69
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 7 pathogenic variants. Next in-frame start position is after 87 codons. Genomic position: 127340570. Lost 0.076 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.3G>T	p.Met1?	start_lost	Exon 2 of 25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.3G>T	p.Met1?	start_lost	Exon 2 of 25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.3G>T	p.Met1?	start_lost	Exon 3 of 26	1		ENSP00000274473.6
MEGF10	ENST00000418761.6	c.3G>T	p.Met1?	start_lost	Exon 3 of 15	1		ENSP00000416284.2
MEGF10	ENST00000508365.5	c.3G>T	p.Met1?	start_lost	Exon 2 of 14	1		ENSP00000423195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

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

Apr 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the MEGF10 mRNA. The next in-frame methionine is located at codon 87. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MEGF10-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the MEGF10 protein in which other variant(s) (p.Arg77Gln) have been observed in individuals with MEGF10-related conditions (PMID: 26802438). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;.;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	.;.;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.13	D
PhyloP100		7.7
PROVEAN	Benign	-0.55	N;N;N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.014	D;D;D;D
Sift4G	Uncertain	0.049	D;T;T;D
Polyphen		0.53	P;P;P;P
Vest4		0.92
MutPred		0.94		Gain of catalytic residue at M1 (P = 0.0275);Gain of catalytic residue at M1 (P = 0.0275);Gain of catalytic residue at M1 (P = 0.0275);Gain of catalytic residue at M1 (P = 0.0275);
MVP		0.79
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.33
gMVP		0.69
Mutation Taster		=30/170	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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

hg19: chr5-126667003;