rs145733370

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS1

The NM_001256545.2(MEGF10):c.50G>A(p.Cys17Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,613,154 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. C17C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

MEGF10
NM_001256545.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 1.09

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.057441413).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00021 (32/152084) while in subpopulation NFE AF = 0.000441 (30/68030). AF 95% confidence interval is 0.000317. There are 0 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.50G>A	p.Cys17Tyr	missense	Exon 2 of 25	NP_001243474.1	Q96KG7-1
MEGF10	NM_032446.3		c.50G>A	p.Cys17Tyr	missense	Exon 3 of 26	NP_115822.1	Q96KG7-1
MEGF10	NM_001308119.2		c.50G>A	p.Cys17Tyr	missense	Exon 3 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.50G>A	p.Cys17Tyr	missense	Exon 2 of 25	ENSP00000423354.2	Q96KG7-1
MEGF10	ENST00000274473.6	TSL:1	c.50G>A	p.Cys17Tyr	missense	Exon 3 of 26	ENSP00000274473.6	Q96KG7-1
MEGF10	ENST00000418761.6	TSL:1	c.50G>A	p.Cys17Tyr	missense	Exon 3 of 15	ENSP00000416284.2	Q96KG7-2

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000195

AC:

AN:

250982

AF XY:

0.000199

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000423

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000251

AC:

367

AN:

1461070

Hom.:

Cov.:

AF XY:

0.000217

AC XY:

158

AN XY:

726848

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33442

American (AMR)

AF:

0.0000224

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000320

AC:

356

AN:

1111420

Other (OTH)

AF:

0.0000994

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000210

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000441

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000328

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000357

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

MEGF10-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.024

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.53

M_CAP

Benign

0.039

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.91

PhyloP100

1.1

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.11

REVEL

Benign

0.19

Sift

Benign

0.74

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.15

MVP

0.12

MPC

0.37

ClinPred

0.015

GERP RS

1.3

Varity_R

0.031

gMVP

0.50

Mutation Taster

=71/29

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over