chr5-127340570-A-G

Position:

• chr5-127340570-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001256545.2(MEGF10):​c.259A>G​(p.Met87Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00071 in 1,612,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (0 hom.)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.25

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27728665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF10	NM_001256545.2	c.259A>G	p.Met87Val	missense_variant	4/25	ENST00000503335.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF10	ENST00000503335.7	c.259A>G	p.Met87Val	missense_variant	4/25	1	NM_001256545.2	P1
MEGF10	ENST00000274473.6	c.259A>G	p.Met87Val	missense_variant	5/26	1		P1
MEGF10	ENST00000418761.6	c.259A>G	p.Met87Val	missense_variant	5/15	1
MEGF10	ENST00000508365.5	c.259A>G	p.Met87Val	missense_variant	4/14	1

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000414 AC: 104 AN: 251250 Hom.: 0 AF XY: 0.000398 AC XY: 54 AN XY: 135794

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000757

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000730 AC: 1066 AN: 1460684 Hom.: 0 Cov.: 30 AF XY: 0.000713 AC XY: 518 AN XY: 726636

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000899

Gnomad4 OTH exome AF: 0.000547

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74446

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000897

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000750 Hom.: 0

Bravo AF: 0.000536

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000461 AC: 56

EpiCase AF: 0.000819

EpiControl AF: 0.000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MEGF10-related myopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2022	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 87 of the MEGF10 protein (p.Met87Val). This variant is present in population databases (rs41298304, gnomAD 0.08%). 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: 350637). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The c.259A>G (p.M87V) alteration is located in exon 5 (coding exon 3) of the MEGF10 gene. This alteration results from a A to G substitution at nucleotide position 259, causing the methionine (M) at amino acid position 87 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 30, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; 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	0.17
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T;.;.;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;.;D;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.8	L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.052	T;D;D;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.99	D;P;P;D
Vest4		0.88
MVP		0.44
MPC		0.77
ClinPred		0.041	T
GERP RS		5.3
Varity_R		0.33
gMVP		0.35

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

Other links and lift over

dbSNP: rs41298304; hg19: chr5-126676262;