5-127290953-G-A

Position:

• chr5-127290953-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

LOC105379199 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.-122G>A		5_prime_UTR_variant	1/25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.-122G>A		5_prime_UTR_variant	1/25	1	NM_001256545.2	ENSP00000423354	P1
MEGF10	ENST00000274473.6	c.-173G>A		5_prime_UTR_variant	1/26	1		ENSP00000274473	P1
MEGF10	ENST00000418761.6	c.-173G>A		5_prime_UTR_variant	1/15	1		ENSP00000416284
MEGF10	ENST00000508365.5	c.-122G>A		5_prime_UTR_variant	1/14	1		ENSP00000423195

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

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.500

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.262

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.414

Gnomad4 EAS AF: 0.306

Gnomad4 SAS AF: 0.379

Gnomad4 FIN AF: 0.353

Gnomad4 NFE AF: 0.459

Gnomad4 OTH AF: 0.418

Alfa AF: 0.443 Hom.: 14552

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

Benign, 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 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.9
DANN	Benign	0.87

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: rs2032834; hg19: chr5-126626645; COSMIC: COSV57246482;