5-127331112-A-G

Variant names:

• chr5-127331112-A-G
• rs80220399
• NM_001256545.2:c.-18-179A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256545.2(MEGF10):​c.-18-179A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 152,284 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: 𝑓 0.018 (71 hom., cov: 32)
• Consequence: MEGF10 NM_001256545.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.214
• Publications: 0 publications found

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]

MEGF10 Gene-Disease associations (from GenCC):

• MEGF10-related myopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 5-127331112-A-G is Benign according to our data. Variant chr5-127331112-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 672379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.-18-179A>G		intron_variant	Intron 1 of 24	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.-18-179A>G		intron_variant	Intron 1 of 24	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.-18-179A>G		intron_variant	Intron 2 of 25	1		ENSP00000274473.6
MEGF10	ENST00000418761.6	c.-18-179A>G		intron_variant	Intron 2 of 14	1		ENSP00000416284.2
MEGF10	ENST00000508365.5	c.-18-179A>G		intron_variant	Intron 1 of 13	1		ENSP00000423195.1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2755 AN: 152166 Hom.: 69 Cov.: 32

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0120

Gnomad ASJ AF: 0.0521

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0909

Gnomad FIN AF: 0.0194

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0192

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0181 AC: 2751 AN: 152284 Hom.: 71 Cov.: 32 AF XY: 0.0199 AC XY: 1484 AN XY: 74462

African (AFR) AF: 0.00556 AC: 231 AN: 41574

American (AMR) AF: 0.0119 AC: 182 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0521 AC: 181 AN: 3472

East Asian (EAS) AF: 0.111 AC: 577 AN: 5180

South Asian (SAS) AF: 0.0908 AC: 438 AN: 4826

European-Finnish (FIN) AF: 0.0194 AC: 206 AN: 10616

Middle Eastern (MID) AF: 0.0959 AC: 28 AN: 292

European-Non Finnish (NFE) AF: 0.0125 AC: 848 AN: 68022

Other (OTH) AF: 0.0194 AC: 41 AN: 2110

Alfa AF: 0.0107 Hom.: 3

Bravo AF: 0.0156

Asia WGS AF: 0.0840 AC: 291 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.7
DANN	Benign	0.70
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs80220399; hg19: chr5-126666804;