5-127369940-G-C

Variant names:

• chr5-127369940-G-C
• rs749238106
• NM_001256545.2:c.350G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001256545.2(MEGF10):​c.350G>C​(p.Arg117Pro) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R117C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.85
• Publications: 2 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.350G>C	p.Arg117Pro	missense_variant	Exon 5 of 25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.350G>C	p.Arg117Pro	missense_variant	Exon 5 of 25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.350G>C	p.Arg117Pro	missense_variant	Exon 6 of 26	1		ENSP00000274473.6
MEGF10	ENST00000418761.6	c.350G>C	p.Arg117Pro	missense_variant	Exon 6 of 15	1		ENSP00000416284.2
MEGF10	ENST00000508365.5	c.350G>C	p.Arg117Pro	missense_variant	Exon 5 of 14	1		ENSP00000423195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D;D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	3.7	H;H;H;H
PhyloP100		9.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.1	D;D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.84
MutPred		0.60		Gain of disorder (P = 0.0579);Gain of disorder (P = 0.0579);Gain of disorder (P = 0.0579);Gain of disorder (P = 0.0579);
MVP		0.47
MPC		1.0
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.72
gMVP		0.80
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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

dbSNP: rs749238106; hg19: chr5-126705632;