rs3812055

Variant names:

• chr5-127396707-G-A
• rs3812055
• NM_001256545.2:c.588G>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.588G>A​(p.Gln196Gln) variant causes a synonymous change. The variant allele was found at a frequency of 0.153 in 1,614,004 control chromosomes in the GnomAD database, including 19,387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2235 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17152 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.89
• Publications: 11 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, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 5-127396707-G-A is Benign according to our data. Variant chr5-127396707-G-A is described in ClinVar as Benign. ClinVar VariationId is 262077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	NM_001256545.2	MANE Select	c.588G>A	p.Gln196Gln	synonymous	Exon 6 of 25	NP_001243474.1
	MEGF10	NM_032446.3		c.588G>A	p.Gln196Gln	synonymous	Exon 7 of 26	NP_115822.1
	MEGF10	NM_001308119.2		c.588G>A	p.Gln196Gln	synonymous	Exon 7 of 15	NP_001295048.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.588G>A	p.Gln196Gln	synonymous	Exon 6 of 25	ENSP00000423354.2
	MEGF10	ENST00000274473.6	TSL:1	c.588G>A	p.Gln196Gln	synonymous	Exon 7 of 26	ENSP00000274473.6
	MEGF10	ENST00000418761.6	TSL:1	c.588G>A	p.Gln196Gln	synonymous	Exon 7 of 15	ENSP00000416284.2

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25459 AN: 152134 Hom.: 2228 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.153

GnomAD2 exomes AF: 0.147 AC: 36777 AN: 250994 AF XY: 0.148

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.0823

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.0987

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.152

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.151 AC: 220773 AN: 1461752 Hom.: 17152 Cov.: 33 AF XY: 0.151 AC XY: 109609 AN XY: 727178

African (AFR) AF: 0.227 AC: 7588 AN: 33480

American (AMR) AF: 0.0843 AC: 3768 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3592 AN: 26136

East Asian (EAS) AF: 0.110 AC: 4356 AN: 39700

South Asian (SAS) AF: 0.168 AC: 14459 AN: 86258

European-Finnish (FIN) AF: 0.170 AC: 9040 AN: 53300

Middle Eastern (MID) AF: 0.0997 AC: 575 AN: 5768

European-Non Finnish (NFE) AF: 0.152 AC: 168628 AN: 1111992

Other (OTH) AF: 0.145 AC: 8767 AN: 60394

GnomAD4 genome AF: 0.167 AC: 25491 AN: 152252 Hom.: 2235 Cov.: 32 AF XY: 0.166 AC XY: 12367 AN XY: 74450

African (AFR) AF: 0.227 AC: 9414 AN: 41536

American (AMR) AF: 0.112 AC: 1709 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 531 AN: 3470

East Asian (EAS) AF: 0.105 AC: 543 AN: 5172

South Asian (SAS) AF: 0.194 AC: 934 AN: 4818

European-Finnish (FIN) AF: 0.164 AC: 1739 AN: 10622

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10203 AN: 68008

Other (OTH) AF: 0.152 AC: 322 AN: 2116

Alfa AF: 0.153 Hom.: 7598

Bravo AF: 0.164

Asia WGS AF: 0.135 AC: 472 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.137

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.5
DANN	Benign	0.83
PhyloP100		5.9
Mutation Taster		=53/47	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: rs3812055; hg19: chr5-126732399; COSMIC: COSV57248707;