5-127396771-G-A

Position:

• chr5-127396771-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 3P and 3B. PM2 PP3 BP4 BP6_Moderate

The NM_001256545.2(MEGF10):​c.652G>A​(p.Gly218Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,612,792 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.16

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.38331097).
• BP6: Variant 5-127396771-G-A is Benign according to our data. Variant chr5-127396771-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 472745.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF10	NM_001256545.2	c.652G>A	p.Gly218Arg	missense_variant	6/25	ENST00000503335.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF10	ENST00000503335.7	c.652G>A	p.Gly218Arg	missense_variant	6/25	1	NM_001256545.2	P1
MEGF10	ENST00000274473.6	c.652G>A	p.Gly218Arg	missense_variant	7/26	1		P1
MEGF10	ENST00000418761.6	c.652G>A	p.Gly218Arg	missense_variant	7/15	1
MEGF10	ENST00000508365.5	c.652G>A	p.Gly218Arg	missense_variant	6/14	1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000446 AC: 111 AN: 248708 Hom.: 0 AF XY: 0.000468 AC XY: 63 AN XY: 134654

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.00325

Gnomad NFE exome AF: 0.000251

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000338 AC: 494 AN: 1460450 Hom.: 0 Cov.: 32 AF XY: 0.000335 AC XY: 243 AN XY: 726366

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00273

Gnomad4 NFE exome AF: 0.000275

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74498

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000164

EpiControl AF: 0.000297

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MEGF10-related myopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.;.;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	.;.;T;T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Pathogenic	4.8	H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.2	D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.82
MutPred		0.93		Loss of catalytic residue at P214 (P = 0.1215);Loss of catalytic residue at P214 (P = 0.1215);Loss of catalytic residue at P214 (P = 0.1215);Loss of catalytic residue at P214 (P = 0.1215);
MVP		0.88
MPC		0.91
ClinPred		0.27	T
GERP RS		4.8
Varity_R		0.41
gMVP		0.66

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: rs148663427; hg19: chr5-126732463;