5-127396570-C-T

Position:

chr5-127396570-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001256545.2(MEGF10):c.451C>T(p.Arg151Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000445 in 1,593,928 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

MEGF10
NM_001256545.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.07

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF10	NM_001256545.2 linkuse as main transcript	c.451C>T	p.Arg151Trp	missense_variant	6/25	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.451C>T	p.Arg151Trp	missense_variant	6/25	1	NM_001256545.2	ENSP00000423354	P1	Q96KG7-1
MEGF10	ENST00000274473.6 linkuse as main transcript	c.451C>T	p.Arg151Trp	missense_variant	7/26	1		ENSP00000274473	P1	Q96KG7-1
MEGF10	ENST00000418761.6 linkuse as main transcript	c.451C>T	p.Arg151Trp	missense_variant	7/15	1		ENSP00000416284		Q96KG7-2
MEGF10	ENST00000508365.5 linkuse as main transcript	c.451C>T	p.Arg151Trp	missense_variant	6/14	1		ENSP00000423195		Q96KG7-2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000337

AC:

AN:

237374

Hom.:

AF XY:

0.0000546

AC XY:

AN XY:

128208

show subpopulations

Gnomad AFR exome

AF:

0.0000642

Gnomad AMR exome

AF:

0.0000301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000478

Gnomad NFE exome

AF:

0.0000374

Gnomad OTH exome

AF:

0.000174

GnomAD4 exome

AF:

0.0000416

AC:

AN:

1441740

Hom.:

Cov.:

AF XY:

0.0000392

AC XY:

AN XY:

714192

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.0000459

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000952

Gnomad4 NFE exome

AF:

0.0000446

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000734

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.451C>T (p.R151W) alteration is located in exon 7 (coding exon 5) of the MEGF10 gene. This alteration results from a C to T substitution at nucleotide position 451, causing the arginine (R) at amino acid position 151 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

MEGF10-related myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 05, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 151 of the MEGF10 protein (p.Arg151Trp). This variant is present in population databases (rs767672691, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with MEGF10-related conditions. ClinVar contains an entry for this variant (Variation ID: 574954). 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 disruptive. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2019

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.42

T;.;.;T

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

.;.;D;D

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.73

D;D;D;D

MetaSVM

Benign

-0.44

MutationAssessor

Pathogenic

3.1

M;M;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0040

D;T;T;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.87

MutPred

0.51

Loss of disorder (P = 0.016);Loss of disorder (P = 0.016);Loss of disorder (P = 0.016);Loss of disorder (P = 0.016);

MVP

0.55

MPC

0.85

ClinPred

0.84

GERP RS

5.0

Varity_R

0.33

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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