rs6595769

Variant names:

• chr5-127398673-C-T
• rs6595769
• NM_001256545.2:c.660-3C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001256545.2(MEGF10):​c.660-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 1,613,692 control chromosomes in the GnomAD database, including 21,498 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3348 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18150 hom.)
• Consequence: MEGF10 NM_001256545.2 splice_region, intron
• Scores: Splicing: ADA: 0.003024
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.97
• Publications: 9 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BP6: Variant 5-127398673-C-T is Benign according to our data. Variant chr5-127398673-C-T is described in ClinVar as Benign. ClinVar VariationId is 262080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.660-3C>T		splice_region_variant, intron_variant	Intron 6 of 24	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.660-3C>T		splice_region_variant, intron_variant	Intron 6 of 24	1	NM_001256545.2	ENSP00000423354.2
MEGF10	ENST00000274473.6	c.660-3C>T		splice_region_variant, intron_variant	Intron 7 of 25	1		ENSP00000274473.6
MEGF10	ENST00000418761.6	c.660-3C>T		splice_region_variant, intron_variant	Intron 7 of 14	1		ENSP00000416284.2
MEGF10	ENST00000508365.5	c.660-3C>T		splice_region_variant, intron_variant	Intron 6 of 13	1		ENSP00000423195.1

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29378 AN: 152056 Hom.: 3333 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.150

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.153 AC: 38556 AN: 251306 AF XY: 0.153

Gnomad AFR exome AF: 0.322

Gnomad AMR exome AF: 0.0873

Gnomad ASJ exome AF: 0.146

Gnomad EAS exome AF: 0.0985

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.154 AC: 224672 AN: 1461520 Hom.: 18150 Cov.: 32 AF XY: 0.153 AC XY: 111256 AN XY: 727076

African (AFR) AF: 0.317 AC: 10611 AN: 33470

American (AMR) AF: 0.0894 AC: 4000 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 3592 AN: 26130

East Asian (EAS) AF: 0.110 AC: 4353 AN: 39696

South Asian (SAS) AF: 0.169 AC: 14530 AN: 86226

European-Finnish (FIN) AF: 0.170 AC: 9058 AN: 53404

Middle Eastern (MID) AF: 0.103 AC: 589 AN: 5722

European-Non Finnish (NFE) AF: 0.152 AC: 168821 AN: 1111772

Other (OTH) AF: 0.151 AC: 9118 AN: 60378

GnomAD4 genome AF: 0.193 AC: 29422 AN: 152172 Hom.: 3348 Cov.: 32 AF XY: 0.191 AC XY: 14233 AN XY: 74400

African (AFR) AF: 0.317 AC: 13155 AN: 41492

American (AMR) AF: 0.121 AC: 1849 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 531 AN: 3468

East Asian (EAS) AF: 0.106 AC: 548 AN: 5186

South Asian (SAS) AF: 0.194 AC: 937 AN: 4818

European-Finnish (FIN) AF: 0.163 AC: 1732 AN: 10604

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.150 AC: 10218 AN: 67998

Other (OTH) AF: 0.168 AC: 354 AN: 2110

Alfa AF: 0.172 Hom.: 1398

Bravo AF: 0.194

Asia WGS AF: 0.139 AC: 488 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.137

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 16% of total chromosomes in ExAC -

MEGF10-related myopathy Benign:2

Feb 03, 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: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	14
DANN	Benign	0.89
PhyloP100		2.0
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0030
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.020		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: rs6595769; hg19: chr5-126734365; COSMIC: COSV57245990;