rs115184652

chr5-127410604-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_001256545.2(MEGF10):c.1130+3G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,597,724 control chromosomes in the GnomAD database, including 4 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 0.00080 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: MEGF10 NM_001256545.2 splice_donor_region, intron
• Scores: Splicing: ADA: 0.001794
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.999

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 5-127410604-G-A is Benign according to our data. Variant chr5-127410604-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252757.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000801 (122/152388) while in subpopulation NFE AF= 0.00134 (91/68048). AF 95% confidence interval is 0.00112. There are 1 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF10	NM_001256545.2	c.1130+3G>A		splice_donor_region_variant, intron_variant		ENST00000503335.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF10	ENST00000503335.7	c.1130+3G>A		splice_donor_region_variant, intron_variant		1	NM_001256545.2	P1

Frequencies

GnomAD3 genomes AF: 0.000801 AC: 122 AN: 152270 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000845 AC: 195 AN: 230642 Hom.: 1 AF XY: 0.000713 AC XY: 89 AN XY: 124896

Gnomad AFR exome AF: 0.000199

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.000612

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00120

GnomAD4 exome AF: 0.00141 AC: 2044 AN: 1445336 Hom.: 3 Cov.: 32 AF XY: 0.00131 AC XY: 941 AN XY: 718388

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.000693

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00169

Gnomad4 OTH exome AF: 0.00160

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152388 Hom.: 1 Cov.: 33 AF XY: 0.000819 AC XY: 61 AN XY: 74512

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00134

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000948

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Sep 18, 2015

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	17
Dann	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.040
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: rs115184652; hg19: chr5-126746296;