Genetic Variant MEGF10:p.Arg349Leu (chr5-127410517-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001256545.2(MEGF10):c.1046G>T(p.Arg349Leu) 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. 15/22 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. R349H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

MEGF10
NM_001256545.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.325

Publications

5 publications found

Variant links:

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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P

MEGF10 links:

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ACMG classification

Classification was made for transcript

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=0.13440394).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MEGF10	NM_001256545.2	MANE Select	c.1046G>T	p.Arg349Leu	missense	Exon 9 of 25	NP_001243474.1	Q96KG7-1
MEGF10	NM_032446.3		c.1046G>T	p.Arg349Leu	missense	Exon 10 of 26	NP_115822.1	Q96KG7-1
MEGF10	NM_001308119.2		c.1046G>T	p.Arg349Leu	missense	Exon 10 of 15	NP_001295048.1	Q96KG7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.1046G>T	p.Arg349Leu	missense	Exon 9 of 25	ENSP00000423354.2	Q96KG7-1
MEGF10	ENST00000274473.6	TSL:1	c.1046G>T	p.Arg349Leu	missense	Exon 10 of 26	ENSP00000274473.6	Q96KG7-1
MEGF10	ENST00000418761.6	TSL:1	c.1046G>T	p.Arg349Leu	missense	Exon 10 of 15	ENSP00000416284.2	Q96KG7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

250664

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.094

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.20

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.67

M_CAP

Benign

0.0047

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

PhyloP100

-0.33

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.074

Sift

Benign

0.25

Sift4G

Benign

0.15

Polyphen

0.0010

Vest4

0.12

MutPred

0.61

Gain of stability (P = 0.0545)

MVP

0.11

MPC

0.28

ClinPred

0.062

GERP RS

-4.7

Varity_R

0.072

gMVP

0.33

Mutation Taster

=95/5

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over