rs12654455

Variant names:

• chr5-127339177-G-A
• rs12654455
• NM_001256545.2:c.174G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-127339177-G-A
• chr5-127339177-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001256545.2(MEGF10):​c.174G>A​(p.Thr58Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,612,208 control chromosomes in the GnomAD database, including 832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T58T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (71 hom., cov: 32)
  • Exomes 𝑓: 0.020 (761 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.36
• Publications: 6 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 5-127339177-G-A is Benign according to our data. Variant chr5-127339177-G-A is described in ClinVar as Benign. ClinVar VariationId is 262064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.105 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.174G>A	p.Thr58Thr	synonymous	Exon 3 of 25	NP_001243474.1	Q96KG7-1
	MEGF10	NM_032446.3		c.174G>A	p.Thr58Thr	synonymous	Exon 4 of 26	NP_115822.1	Q96KG7-1
	MEGF10	NM_001308119.2		c.174G>A	p.Thr58Thr	synonymous	Exon 4 of 15	NP_001295048.1	Q96KG7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.174G>A	p.Thr58Thr	synonymous	Exon 3 of 25	ENSP00000423354.2	Q96KG7-1
	MEGF10	ENST00000274473.6	TSL:1	c.174G>A	p.Thr58Thr	synonymous	Exon 4 of 26	ENSP00000274473.6	Q96KG7-1
	MEGF10	ENST00000418761.6	TSL:1	c.174G>A	p.Thr58Thr	synonymous	Exon 4 of 15	ENSP00000416284.2	Q96KG7-2

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2761 AN: 151954 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.00565

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.0907

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0299 AC: 7505 AN: 250732 AF XY: 0.0328

Gnomad AFR exome AF: 0.00456

Gnomad AMR exome AF: 0.0108

Gnomad ASJ exome AF: 0.0498

Gnomad EAS exome AF: 0.107

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.0133

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0196 AC: 28552 AN: 1460136 Hom.: 761 Cov.: 29 AF XY: 0.0215 AC XY: 15596 AN XY: 726378

African (AFR) AF: 0.00515 AC: 172 AN: 33402

American (AMR) AF: 0.0106 AC: 474 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0486 AC: 1267 AN: 26078

East Asian (EAS) AF: 0.111 AC: 4405 AN: 39640

South Asian (SAS) AF: 0.0810 AC: 6979 AN: 86124

European-Finnish (FIN) AF: 0.0165 AC: 880 AN: 53398

Middle Eastern (MID) AF: 0.0304 AC: 175 AN: 5752

European-Non Finnish (NFE) AF: 0.0115 AC: 12745 AN: 1110790

Other (OTH) AF: 0.0241 AC: 1455 AN: 60278

GnomAD4 genome AF: 0.0181 AC: 2755 AN: 152072 Hom.: 71 Cov.: 32 AF XY: 0.0201 AC XY: 1493 AN XY: 74316

African (AFR) AF: 0.00561 AC: 233 AN: 41502

American (AMR) AF: 0.0117 AC: 179 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 181 AN: 3470

East Asian (EAS) AF: 0.113 AC: 582 AN: 5172

South Asian (SAS) AF: 0.0906 AC: 436 AN: 4814

European-Finnish (FIN) AF: 0.0195 AC: 206 AN: 10570

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0125 AC: 851 AN: 67982

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.0155 Hom.: 67

Bravo AF: 0.0155

Asia WGS AF: 0.0690 AC: 239 AN: 3478

EpiCase AF: 0.0145

EpiControl AF: 0.0133

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	MEGF10-related myopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.0
DANN	Benign	0.86
PhyloP100		-2.4
Mutation Taster		=100/0	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: rs12654455; hg19: chr5-126674869; COSMIC: COSV57246310;