chr5-127339238-C-G

Position:

• chr5-127339238-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001256545.2(MEGF10):​c.218+17C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,569,170 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (18 hom.)
• Consequence: MEGF10 NM_001256545.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.231

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 5-127339238-C-G is Benign according to our data. Variant chr5-127339238-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 262070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00247 (376/152120) while in subpopulation NFE AF= 0.0038 (258/67984). AF 95% confidence interval is 0.00341. There are 1 homozygotes in gnomad4. There are 186 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEGF10	NM_001256545.2	c.218+17C>G		intron_variant		ENST00000503335.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEGF10	ENST00000503335.7	c.218+17C>G		intron_variant		1	NM_001256545.2	P1
MEGF10	ENST00000274473.6	c.218+17C>G		intron_variant		1		P1
MEGF10	ENST00000418761.6	c.218+17C>G		intron_variant		1
MEGF10	ENST00000508365.5	c.218+17C>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00247 AC: 376 AN: 152002 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00322

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00379

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00232 AC: 575 AN: 247516 Hom.: 2 AF XY: 0.00224 AC XY: 300 AN XY: 133704

Gnomad AFR exome AF: 0.000927

Gnomad AMR exome AF: 0.00181

Gnomad ASJ exome AF: 0.00453

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000699

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00350

GnomAD4 exome AF: 0.00358 AC: 5069 AN: 1417050 Hom.: 18 Cov.: 23 AF XY: 0.00340 AC XY: 2405 AN XY: 707404

Gnomad4 AFR exome AF: 0.000524

Gnomad4 AMR exome AF: 0.00199

Gnomad4 ASJ exome AF: 0.00444

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000563

Gnomad4 NFE exome AF: 0.00428

Gnomad4 OTH exome AF: 0.00376

GnomAD4 genome AF: 0.00247 AC: 376 AN: 152120 Hom.: 1 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74366

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00380

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00294 Hom.: 1

Bravo AF: 0.00267

Asia WGS AF: 0.000289 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MEGF10-related myopathy Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 31, 2018	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.28
DANN	Benign	0.36

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: rs72786483; hg19: chr5-126674930;