NM_001256545.2:c.984C>T

Variant names:

• chr5-127410455-C-T
• rs35550094
• NM_001256545.2:c.984C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001256545.2(MEGF10):​c.984C>T​(p.Asn328Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00442 in 1,614,190 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (51 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.729
• Publications: 2 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 5-127410455-C-T is Benign according to our data. Variant chr5-127410455-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.729 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0508 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.984C>T	p.Asn328Asn	synonymous	Exon 9 of 25	NP_001243474.1
	MEGF10	NM_032446.3		c.984C>T	p.Asn328Asn	synonymous	Exon 10 of 26	NP_115822.1
	MEGF10	NM_001308119.2		c.984C>T	p.Asn328Asn	synonymous	Exon 10 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.984C>T	p.Asn328Asn	synonymous	Exon 9 of 25	ENSP00000423354.2
	MEGF10	ENST00000274473.6	TSL:1	c.984C>T	p.Asn328Asn	synonymous	Exon 10 of 26	ENSP00000274473.6
	MEGF10	ENST00000418761.6	TSL:1	c.984C>T	p.Asn328Asn	synonymous	Exon 10 of 15	ENSP00000416284.2

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2302 AN: 152208 Hom.: 41 Cov.: 33

Gnomad AFR AF: 0.0475

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00579 AC: 1456 AN: 251420 AF XY: 0.00497

Gnomad AFR exome AF: 0.0495

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.0197

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00331 AC: 4836 AN: 1461864 Hom.: 51 Cov.: 31 AF XY: 0.00320 AC XY: 2328 AN XY: 727228

African (AFR) AF: 0.0528 AC: 1769 AN: 33480

American (AMR) AF: 0.00380 AC: 170 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0229 AC: 599 AN: 26136

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39700

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86258

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53396

Middle Eastern (MID) AF: 0.0132 AC: 76 AN: 5764

European-Non Finnish (NFE) AF: 0.00158 AC: 1757 AN: 1112010

Other (OTH) AF: 0.00649 AC: 392 AN: 60396

GnomAD4 genome AF: 0.0151 AC: 2306 AN: 152326 Hom.: 41 Cov.: 33 AF XY: 0.0151 AC XY: 1127 AN XY: 74488

African (AFR) AF: 0.0474 AC: 1971 AN: 41572

American (AMR) AF: 0.00601 AC: 92 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 76 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00204 AC: 139 AN: 68034

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.00957 Hom.: 12

Bravo AF: 0.0173

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00450

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.062
DANN	Benign	0.89
PhyloP100		-0.73
Mutation Taster		=97/3	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: rs35550094; hg19: chr5-126746147; COSMIC: COSV106088308;