5-127422681-C-T

Variant names:

• chr5-127422681-C-T
• rs114704569
• NM_001256545.2:c.1602C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001256545.2(MEGF10):​c.1602C>T​(p.Tyr534Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,613,786 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.256
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 5-127422681-C-T is Benign according to our data. Variant chr5-127422681-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 350652.
• BP7: Synonymous conserved (PhyloP=-0.256 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00122 (186/152236) while in subpopulation NFE AF = 0.00209 (142/68014). AF 95% confidence interval is 0.00181. There are 1 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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.1602C>T	p.Tyr534Tyr	synonymous	Exon 13 of 25	NP_001243474.1
	MEGF10	NM_032446.3		c.1602C>T	p.Tyr534Tyr	synonymous	Exon 14 of 26	NP_115822.1
	MEGF10	NM_001308119.2		c.1602C>T	p.Tyr534Tyr	synonymous	Exon 14 of 15	NP_001295048.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.1602C>T	p.Tyr534Tyr	synonymous	Exon 13 of 25	ENSP00000423354.2
	MEGF10	ENST00000274473.6	TSL:1	c.1602C>T	p.Tyr534Tyr	synonymous	Exon 14 of 26	ENSP00000274473.6
	MEGF10	ENST00000418761.6	TSL:1	c.1602C>T	p.Tyr534Tyr	synonymous	Exon 14 of 15	ENSP00000416284.2

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00120 AC: 301 AN: 250300 AF XY: 0.00121

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000983

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00202 AC: 2959 AN: 1461550 Hom.: 6 Cov.: 30 AF XY: 0.00195 AC XY: 1419 AN XY: 727100

African (AFR) AF: 0.000568 AC: 19 AN: 33476

American (AMR) AF: 0.00136 AC: 61 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.000904 AC: 78 AN: 86246

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53408

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5766

European-Non Finnish (NFE) AF: 0.00239 AC: 2652 AN: 1111722

Other (OTH) AF: 0.00217 AC: 131 AN: 60382

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152236 Hom.: 1 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74426

African (AFR) AF: 0.000458 AC: 19 AN: 41530

American (AMR) AF: 0.00118 AC: 18 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00209 AC: 142 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00178 Hom.: 0

Bravo AF: 0.00123

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

MEGF10-related myopathy Uncertain:1 Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

not provided Benign:2

Jul 05, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEGF10: BP4, BP7

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.80
DANN	Benign	0.57
PhyloP100		-0.26
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: rs114704569; hg19: chr5-126758373;