Genetic Variant MEGF10:p.Ser336Arg (chr5-127410479-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001256545.2(MEGF10):c.1008C>A(p.Ser336Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S336N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MEGF10
NM_001256545.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.18

Publications

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

MEGF10 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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
MEGF10	NM_001256545.2	MANE Select	c.1008C>A	p.Ser336Arg	missense	Exon 9 of 25	NP_001243474.1
MEGF10	NM_032446.3		c.1008C>A	p.Ser336Arg	missense	Exon 10 of 26	NP_115822.1
MEGF10	NM_001308119.2		c.1008C>A	p.Ser336Arg	missense	Exon 10 of 15	NP_001295048.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.1008C>A	p.Ser336Arg	missense	Exon 9 of 25	ENSP00000423354.2
MEGF10	ENST00000274473.6	TSL:1	c.1008C>A	p.Ser336Arg	missense	Exon 10 of 26	ENSP00000274473.6
MEGF10	ENST00000418761.6	TSL:1	c.1008C>A	p.Ser336Arg	missense	Exon 10 of 15	ENSP00000416284.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461786

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Pathogenic

0.79

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Benign

-0.31

CADD

Benign

0.070

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.046

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.15

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.8

PhyloP100

-2.2

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.32

Sift

Uncertain

0.011

Sift4G

Uncertain

0.020

Polyphen

0.79

Vest4

0.65

MutPred

0.67

Loss of glycosylation at S336 (P = 0.0196)

MVP

0.33

MPC

0.25

ClinPred

0.88

GERP RS

-8.1

Varity_R

0.32

gMVP

0.67

Mutation Taster

=28/72

disease causing

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over