5-127339238-C-G

Variant names:

• chr5-127339238-C-G
• rs72786483
• NM_001256545.2:c.218+17C>G

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: -0.231
• 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=-0.89).
• BP6: Variant 5-127339238-C-G is Benign according to our data. Variant chr5-127339238-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 18 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.218+17C>G		intron	N/A	NP_001243474.1
	MEGF10	NM_032446.3		c.218+17C>G		intron	N/A	NP_115822.1
	MEGF10	NM_001308119.2		c.218+17C>G		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.218+17C>G		intron	N/A	ENSP00000423354.2
	MEGF10	ENST00000274473.6	TSL:1	c.218+17C>G		intron	N/A	ENSP00000274473.6
	MEGF10	ENST00000418761.6	TSL:1	c.218+17C>G		intron	N/A	ENSP00000416284.2

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

GnomAD2 exomes AF: 0.00232 AC: 575 AN: 247516 AF XY: 0.00224

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 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

African (AFR) AF: 0.000524 AC: 17 AN: 32422

American (AMR) AF: 0.00199 AC: 88 AN: 44118

Ashkenazi Jewish (ASJ) AF: 0.00444 AC: 114 AN: 25690

East Asian (EAS) AF: 0.00 AC: 0 AN: 39354

South Asian (SAS) AF: 0.00 AC: 0 AN: 84662

European-Finnish (FIN) AF: 0.000563 AC: 30 AN: 53244

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5656

European-Non Finnish (NFE) AF: 0.00428 AC: 4598 AN: 1073082

Other (OTH) AF: 0.00376 AC: 221 AN: 58822

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

African (AFR) AF: 0.00101 AC: 42 AN: 41520

American (AMR) AF: 0.00321 AC: 49 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10598

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

European-Non Finnish (NFE) AF: 0.00380 AC: 258 AN: 67984

Other (OTH) AF: 0.00425 AC: 9 AN: 2116

Alfa AF: 0.00294 Hom.: 1

Bravo AF: 0.00267

Asia WGS AF: 0.000289 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	MEGF10-related myopathy (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.28
DANN	Benign	0.36
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism

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: rs72786483; hg19: chr5-126674930;