rs538399152

Variant names:

• chr5-127339115-T-TC
• rs538399152
• NM_001256545.2:c.117-5_117-4insC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001256545.2(MEGF10):​c.117-5_117-4insC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000507 in 1,567,582 control chromosomes in the GnomAD database, including 10 homozygotes. 1/1 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 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (8 hom.)
• Consequence: MEGF10 NM_001256545.2 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.380
• Publications: 1 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 -9 ACMG points.

• BP6: Variant 5-127339115-T-TC is Benign according to our data. Variant chr5-127339115-T-TC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 350635.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00102 (156/152234) while in subpopulation EAS AF = 0.0272 (141/5184). AF 95% confidence interval is 0.0235. There are 2 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256545.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	NM_001256545.2	MANE Select	c.117-5_117-4insC		splice_region intron	N/A	NP_001243474.1
	MEGF10	NM_032446.3		c.117-5_117-4insC		splice_region intron	N/A	NP_115822.1
	MEGF10	NM_001308119.2		c.117-5_117-4insC		splice_region intron	N/A	NP_001295048.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.117-5_117-4insC		splice_region intron	N/A	ENSP00000423354.2
	MEGF10	ENST00000274473.6	TSL:1	c.117-5_117-4insC		splice_region intron	N/A	ENSP00000274473.6
	MEGF10	ENST00000418761.6	TSL:1	c.117-5_117-4insC		splice_region intron	N/A	ENSP00000416284.2

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152116 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000591

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0269

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00170 AC: 411 AN: 241680 AF XY: 0.00155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000929

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0225

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000686

GnomAD4 exome AF: 0.000451 AC: 638 AN: 1415348 Hom.: 8 Cov.: 25 AF XY: 0.000425 AC XY: 300 AN XY: 705060

African (AFR) AF: 0.00 AC: 0 AN: 32326

American (AMR) AF: 0.000117 AC: 5 AN: 42758

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25356

East Asian (EAS) AF: 0.0129 AC: 501 AN: 38972

South Asian (SAS) AF: 0.000298 AC: 24 AN: 80522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52612

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5628

European-Non Finnish (NFE) AF: 0.00000834 AC: 9 AN: 1078620

Other (OTH) AF: 0.00167 AC: 98 AN: 58554

GnomAD4 genome AF: 0.00102 AC: 156 AN: 152234 Hom.: 2 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74426

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.000590 AC: 9 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0272 AC: 141 AN: 5184

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67994

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000260 Hom.: 1

Bravo AF: 0.000767

Asia WGS AF: 0.00664 AC: 23 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	MEGF10-related myopathy (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs538399152; hg19: chr5-126674807;