5-127396571-G-C

Position:

• chr5-127396571-G-C

Variant summary

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

The NM_001256545.2(MEGF10):​c.452G>C​(p.Arg151Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,442,380 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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.452G>C	p.Arg151Pro	missense_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.452G>C	p.Arg151Pro	missense_variant	6/25	1	NM_001256545.2	ENSP00000423354	P1
MEGF10	ENST00000274473.6	c.452G>C	p.Arg151Pro	missense_variant	7/26	1		ENSP00000274473	P1
MEGF10	ENST00000418761.6	c.452G>C	p.Arg151Pro	missense_variant	7/15	1		ENSP00000416284
MEGF10	ENST00000508365.5	c.452G>C	p.Arg151Pro	missense_variant	6/14	1		ENSP00000423195

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1442380 Hom.: 0 Cov.: 31 AF XY: 0.00000280 AC XY: 2 AN XY: 714624

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.045	T;.;.;T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.69	.;.;T;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.64	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Uncertain	0.47
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.26	T;T;T;T
Polyphen		1.0	D;P;P;D
Vest4		0.82
MutPred		0.52		Gain of disorder (P = 0.1019);Gain of disorder (P = 0.1019);Gain of disorder (P = 0.1019);Gain of disorder (P = 0.1019);
MVP		0.47
MPC		1.0
ClinPred		0.86	D
GERP RS		5.8
Varity_R		0.36
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78069165; hg19: chr5-126732263;