5-127290953-G-A

Variant names:

• chr5-127290953-G-A
• rs2032834
• NM_001256545.2:c.-122G>A

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.-122G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 152,188 control chromosomes in the GnomAD database, including 11,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11816 hom., cov: 33)
  • Exomes 𝑓: 0.48 (7 hom.)
• Consequence: MEGF10 NM_001256545.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0370
• Publications: 7 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

LOC105379199 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 5-127290953-G-A is Benign according to our data. Variant chr5-127290953-G-A is described in ClinVar as [Benign]. Clinvar id is 350631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.-122G>A		5_prime_UTR_variant	Exon 1 of 25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.-122G>A		5_prime_UTR_variant	Exon 1 of 25	1	NM_001256545.2	ENSP00000423354.2

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58561 AN: 152002 Hom.: 11815 Cov.: 33

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.611

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.416

GnomAD4 exome AF: 0.484 AC: 31 AN: 64 Hom.: 7 Cov.: 0 AF XY: 0.519 AC XY: 28 AN XY: 54

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 7 AN: 14

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 22 AN: 44

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.385 AC: 58578 AN: 152124 Hom.: 11816 Cov.: 33 AF XY: 0.381 AC XY: 28361 AN XY: 74366

African (AFR) AF: 0.262 AC: 10878 AN: 41502

American (AMR) AF: 0.414 AC: 6338 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1436 AN: 3470

East Asian (EAS) AF: 0.306 AC: 1584 AN: 5170

South Asian (SAS) AF: 0.379 AC: 1826 AN: 4824

European-Finnish (FIN) AF: 0.353 AC: 3734 AN: 10572

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.459 AC: 31188 AN: 67974

Other (OTH) AF: 0.418 AC: 881 AN: 2110

Alfa AF: 0.434 Hom.: 18492

Bravo AF: 0.382

Asia WGS AF: 0.365 AC: 1272 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MEGF10-related myopathy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.9
DANN	Benign	0.87
PhyloP100		0.037
PromoterAI		-0.020	Neutral
Mutation Taster		=299/1	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: rs2032834; hg19: chr5-126626645; COSMIC: COSV57246482;