5-127331312-G-T

Variant names:

• chr5-127331312-G-T
• rs1024164094
• NM_001256545.2:c.4G>T

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.4G>T​(p.Val2Phe) 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. V2I) 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: 0.356
• 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: 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=0.09155989).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.4G>T	p.Val2Phe	missense_variant	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.4G>T	p.Val2Phe	missense_variant	Exon 2 of 25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.4G>T	p.Val2Phe	missense_variant	Exon 3 of 26	1		ENSP00000274473.6
MEGF10	ENST00000418761.6	c.4G>T	p.Val2Phe	missense_variant	Exon 3 of 15	1		ENSP00000416284.2
MEGF10	ENST00000508365.5	c.4G>T	p.Val2Phe	missense_variant	Exon 2 of 14	1		ENSP00000423195.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	6.7
DANN	Benign	0.97
DEOGEN2	Benign	0.019	T;.;.;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.73
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.55	.;.;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.092	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N;N;N;N
PhyloP100		0.36
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.34	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.20	T;T;T;T
Sift4G	Benign	0.30	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.15
MutPred		0.36		Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.13
MPC		0.29
ClinPred		0.036	T
GERP RS		0.13
Varity_R		0.045
gMVP		0.70
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs1024164094; hg19: chr5-126667004;