5-127410571-G-C

Variant names:

• chr5-127410571-G-C
• rs371522377
• NM_001256545.2:c.1100G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001256545.2(MEGF10):​c.1100G>C​(p.Arg367Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. R367W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.283
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1497131).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256545.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	NM_001256545.2	MANE Select	c.1100G>C	p.Arg367Pro	missense	Exon 9 of 25	NP_001243474.1
	MEGF10	NM_032446.3		c.1100G>C	p.Arg367Pro	missense	Exon 10 of 26	NP_115822.1
	MEGF10	NM_001308119.2		c.1100G>C	p.Arg367Pro	missense	Exon 10 of 15	NP_001295048.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.1100G>C	p.Arg367Pro	missense	Exon 9 of 25	ENSP00000423354.2
	MEGF10	ENST00000274473.6	TSL:1	c.1100G>C	p.Arg367Pro	missense	Exon 10 of 26	ENSP00000274473.6
	MEGF10	ENST00000418761.6	TSL:1	c.1100G>C	p.Arg367Pro	missense	Exon 10 of 15	ENSP00000416284.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	4.8
DANN	Benign	0.77
DEOGEN2	Benign	0.0095	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.30	N
PhyloP100		0.28
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.15
Sift	Benign	0.73	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.55		Gain of ubiquitination at K366 (P = 0.0725)
MVP		0.85
MPC		0.59
ClinPred		0.24	T
GERP RS		1.7
Varity_R		0.12
gMVP		0.76
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs371522377; hg19: chr5-126746263;