chr5-127455393-C-T

Position:

• chr5-127455393-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001256545.2(MEGF10):​c.3026-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,611,820 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (11 hom.)
• Consequence: MEGF10 NM_001256545.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001937
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.32

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 5-127455393-C-T is Benign according to our data. Variant chr5-127455393-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 350669.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}. Variant chr5-127455393-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00104 (158/152310) while in subpopulation AMR AF= 0.00209 (32/15306). AF 95% confidence interval is 0.00152. There are 1 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.3026-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.3026-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001256545.2	ENSP00000423354	P1
MEGF10	ENST00000274473.6	c.3026-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000274473	P1
MEGF10	ENST00000510828.5	n.525-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5
MEGF10	ENST00000515622.1	n.227-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00155 AC: 385 AN: 248688 Hom.: 2 AF XY: 0.00174 AC XY: 234 AN XY: 134632

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.00719

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000826

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.00330

GnomAD4 exome AF: 0.00121 AC: 1772 AN: 1459510 Hom.: 11 Cov.: 30 AF XY: 0.00133 AC XY: 965 AN XY: 726078

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.00211

Gnomad4 ASJ exome AF: 0.00645

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000944

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.00277

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74476

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00193 Hom.: 1

Bravo AF: 0.00134

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00285

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	MEGF10: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

MEGF10-related myopathy Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
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. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 03, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 28, 2017	- -

MEGF10-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	3.3
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.018
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: rs185480820; hg19: chr5-126791085;