chr5-127420181-G-A

Position:

• chr5-127420181-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP3 BP4_Moderate BP6 BS1 BS2

The NM_001256545.2(MEGF10):​c.1564G>A​(p.Gly522Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0039 in 1,614,130 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (24 hom.)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 9.95

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 Benign. Variant got -10 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.15944293).
• BP6: Variant 5-127420181-G-A is Benign according to our data. Variant chr5-127420181-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 350651.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}. Variant chr5-127420181-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00228 (347/152282) while in subpopulation NFE AF= 0.00397 (270/68028). AF 95% confidence interval is 0.00358. There are 0 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.1564G>A	p.Gly522Arg	missense_variant	12/25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.1564G>A	p.Gly522Arg	missense_variant	12/25	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.1564G>A	p.Gly522Arg	missense_variant	13/26	1		ENSP00000274473.6
MEGF10	ENST00000418761.6	c.1564G>A	p.Gly522Arg	missense_variant	13/15	1		ENSP00000416284.2
MEGF10	ENST00000508365.5	c.1564G>A	p.Gly522Arg	missense_variant	12/14	1		ENSP00000423195.1

Frequencies

GnomAD3 genomes AF: 0.00228 AC: 347 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00224 AC: 562 AN: 250462 Hom.: 3 AF XY: 0.00220 AC XY: 298 AN XY: 135364

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000979

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00416

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00406 AC: 5942 AN: 1461848 Hom.: 24 Cov.: 30 AF XY: 0.00388 AC XY: 2819 AN XY: 727216

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000674

Gnomad4 NFE exome AF: 0.00505

Gnomad4 OTH exome AF: 0.00291

GnomAD4 genome AF: 0.00228 AC: 347 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.00195 AC XY: 145 AN XY: 74480

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00397

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00310 Hom.: 1

Bravo AF: 0.00247

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00236 AC: 286

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00427

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MEGF10: BS2 -

MEGF10-related myopathy Uncertain:1 Benign: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 25, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.1564G>A (p.G522R) alteration is located in exon 13 (coding exon 11) of the MEGF10 gene. This alteration results from a G to A substitution at nucleotide position 1564, causing the glycine (G) at amino acid position 522 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	D;.;.;D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	.;.;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H;H;H;H
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.0	D;D;D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.95
MutPred		0.78		Gain of ubiquitination at K524 (P = 0.0931);Gain of ubiquitination at K524 (P = 0.0931);Gain of ubiquitination at K524 (P = 0.0931);Gain of ubiquitination at K524 (P = 0.0931);
MVP		0.80
MPC		0.89
ClinPred		0.21	T
GERP RS		5.7
Varity_R		0.82
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs140563851; hg19: chr5-126755873;