rs78847357

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000503335.7(MEGF10):c.1046G>A(p.Arg349His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,842 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0053 ( 7 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 5 hom. )

Consequence

MEGF10
ENST00000503335.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.325

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007239789).

BP6

Variant 5-127410517-G-A is Benign according to our data. Variant chr5-127410517-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 262059.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00532 (810/152348) while in subpopulation AFR AF= 0.0173 (718/41580). AF 95% confidence interval is 0.0162. There are 7 homozygotes in gnomad4. There are 386 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF10	NM_001256545.2 linkuse as main transcript	c.1046G>A	p.Arg349His	missense_variant	9/25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7 linkuse as main transcript	c.1046G>A	p.Arg349His	missense_variant	9/25	1	NM_001256545.2	ENSP00000423354	P1	Q96KG7-1

Frequencies

GnomAD3 genomes

AF:

0.00531

AC:

808

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0173

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00451

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00716

GnomAD3 exomes

AF:

0.00138

AC:

347

AN:

250664

Hom.:

AF XY:

0.000974

AC XY:

132

AN XY:

135540

show subpopulations

Gnomad AFR exome

AF:

0.0173

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000589

AC:

861

AN:

1461494

Hom.:

Cov.:

AF XY:

0.000509

AC XY:

370

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.0191

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000558

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.00532

AC:

810

AN:

152348

Hom.:

Cov.:

AF XY:

0.00518

AC XY:

386

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.0173

Gnomad4 AMR

AF:

0.00451

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00709

Alfa

AF:

0.000642

Hom.:

Bravo

AF:

0.00591

ESP6500AA

AF:

0.0200

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00166

AC:

202

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

MEGF10-related myopathy

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.10

DANN

Benign

0.94

DEOGEN2

Benign

0.012

T;.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.094

LIST_S2

Benign

0.49

.;.;T;T

MetaRNN

Benign

0.0072

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.42

N;N;N;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.58

N;N;N;N

REVEL

Benign

0.052

Sift

Benign

0.43

T;T;T;T

Sift4G

Benign

0.35

T;T;T;T

Polyphen

0.0010

B;B;B;B

Vest4

0.094

MVP

0.26

MPC

0.27

ClinPred

0.00048

GERP RS

-4.7

Varity_R

0.020

gMVP

0.21

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over