rs3812054

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001256545.2(MEGF10):c.616G>A(p.Val206Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,613,958 control chromosomes in the GnomAD database, including 13,248 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 958 hom., cov: 32)

Exomes 𝑓: 0.13 ( 12290 hom. )

Consequence

MEGF10
NM_001256545.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.601

Publications

23 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015771091).

BP6

Variant 5-127396735-G-A is Benign according to our data. Variant chr5-127396735-G-A is described in ClinVar as Benign. ClinVar VariationId is 262079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2 link	c.616G>A	p.Val206Ile	missense_variant	Exon 6 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.616G>A	p.Val206Ile	missense_variant	Exon 6 of 25	1	NM_001256545.2	ENSP00000423354.2	Q96KG7-1
MEGF10	ENST00000274473.6 link	c.616G>A	p.Val206Ile	missense_variant	Exon 7 of 26	1		ENSP00000274473.6	Q96KG7-1
MEGF10	ENST00000418761.6 link	c.616G>A	p.Val206Ile	missense_variant	Exon 7 of 15	1		ENSP00000416284.2	Q96KG7-2
MEGF10	ENST00000508365.5 link	c.616G>A	p.Val206Ile	missense_variant	Exon 6 of 14	1		ENSP00000423195.1	Q96KG7-2

Frequencies

GnomAD3 genomes

AF:

0.108

AC:

16401

AN:

152160

Hom.:

956

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0708

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.0830

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.0586

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.106

GnomAD2 exomes

AF:

0.110

AC:

27684

AN:

250708

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.0679

Gnomad AMR exome

AF:

0.0610

Gnomad ASJ exome

AF:

0.0968

Gnomad EAS exome

AF:

0.0506

Gnomad FIN exome

AF:

0.148

Gnomad NFE exome

AF:

0.137

Gnomad OTH exome

AF:

0.116

GnomAD4 exome

AF:

0.127

AC:

185530

AN:

1461680

Hom.:

12290

Cov.:

AF XY:

0.126

AC XY:

91700

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.0668

AC:

2235

AN:

33480

American (AMR)

AF:

0.0632

AC:

2828

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0900

AC:

2351

AN:

26134

East Asian (EAS)

AF:

0.0719

AC:

2853

AN:

39700

South Asian (SAS)

AF:

0.103

AC:

8861

AN:

86258

European-Finnish (FIN)

AF:

0.152

AC:

8122

AN:

53266

Middle Eastern (MID)

AF:

0.0685

AC:

395

AN:

5768

European-Non Finnish (NFE)

AF:

0.136

AC:

151085

AN:

1111958

Other (OTH)

AF:

0.113

AC:

6800

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

9069

18138

27208

36277

45346

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5312

10624

15936

21248

26560

<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

AF:

0.108

AC:

16408

AN:

152278

Hom.:

958

Cov.:

AF XY:

0.107

AC XY:

7979

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0707

AC:

2940

AN:

41560

American (AMR)

AF:

0.0829

AC:

1269

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.103

AC:

356

AN:

3468

East Asian (EAS)

AF:

0.0585

AC:

303

AN:

5180

South Asian (SAS)

AF:

0.117

AC:

563

AN:

4822

European-Finnish (FIN)

AF:

0.144

AC:

1527

AN:

10612

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.135

AC:

9174

AN:

68012

Other (OTH)

AF:

0.106

AC:

224

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

777

1554

2330

3107

3884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

376

564

752

940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.120

Hom.:

4315

Bravo

AF:

0.0987

TwinsUK

AF:

0.139

AC:

515

ALSPAC

AF:

0.134

AC:

516

ESP6500AA

AF:

0.0654

AC:

288

ESP6500EA

AF:

0.130

AC:

1120

ExAC

AF:

0.113

AC:

13766

Asia WGS

AF:

0.0770

AC:

269

AN:

3478

EpiCase

AF:

0.119

EpiControl

AF:

0.122

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 05, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

MEGF10-related myopathy

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

1.2

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.015

T;.;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.65

.;.;T;T

MetaRNN

Benign

0.0016

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.86

L;L;L;L

PhyloP100

0.60

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.25

N;N;N;N

REVEL

Benign

0.013

Sift

Benign

0.40

T;T;T;T

Sift4G

Benign

0.21

T;T;T;T

Polyphen

0.0030

B;B;B;B

Vest4

0.042

MPC

0.18

ClinPred

0.00017

GERP RS

0.79

Varity_R

0.0097

gMVP

0.052

Mutation Taster

=99/1

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over