5-127454588-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001256545.2(MEGF10):c.3003C>G(p.Ser1001Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S1001S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

MEGF10
NM_001256545.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.440

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2 link	c.3003C>G	p.Ser1001Arg	missense_variant	Exon 23 of 25	ENST00000503335.7	NP_001243474.1	Q96KG7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MEGF10	ENST00000503335.7 link	c.3003C>G	p.Ser1001Arg	missense_variant	Exon 23 of 25	1	NM_001256545.2	ENSP00000423354.2	Q96KG7-1
MEGF10	ENST00000274473.6 link	c.3003C>G	p.Ser1001Arg	missense_variant	Exon 24 of 26	1		ENSP00000274473.6	Q96KG7-1
MEGF10	ENST00000510828.5 link	n.502C>G		non_coding_transcript_exon_variant	Exon 5 of 6	5
MEGF10	ENST00000515622.1 link	n.204C>G		non_coding_transcript_exon_variant	Exon 3 of 5	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000407

AC:

AN:

245676

AF XY:

0.00000752

show subpopulations

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:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1455568

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

723896

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33084

American (AMR)

AF:

0.00

AC:

AN:

43804

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25954

East Asian (EAS)

AF:

0.00

AC:

AN:

39484

South Asian (SAS)

AF:

0.00

AC:

AN:

84546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1109616

Other (OTH)

AF:

0.00

AC:

AN:

60092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.0000103

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

MEGF10-related myopathy

Uncertain:1

Apr 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine with arginine at codon 1001 of the MEGF10 protein (p.Ser1001Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine. This variant is present in population databases (rs35159176, ExAC 0.002%). This variant has not been reported in the literature in individuals with MEGF10-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.024

T;T

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.73

.;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.087

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;L

PhyloP100

-0.44

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.67

N;N

REVEL

Benign

0.17

Sift

Benign

0.92

T;T

Sift4G

Benign

0.64

T;T

Polyphen

0.0

B;B

Vest4

0.31

MutPred

0.40

Gain of MoRF binding (P = 0.0186);Gain of MoRF binding (P = 0.0186);

MVP

0.15

MPC

0.25

ClinPred

0.11

GERP RS

1.4

Varity_R

0.033

gMVP

0.44

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.59

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.59

Position offset: -1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over