rs17164938

Variant names:

• chr5-127455537-G-A
• rs17164938
• NM_001256545.2:c.3162G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-127455537-G-A
• chr5-127455537-G-C
• chr5-127455537-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001256545.2(MEGF10):​c.3162G>A​(p.Pro1054Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 1,613,852 control chromosomes in the GnomAD database, including 914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (82 hom., cov: 32)
  • Exomes 𝑓: 0.032 (832 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.53
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 5-127455537-G-A is Benign according to our data. Variant chr5-127455537-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.53 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0324 (4932/152138) while in subpopulation EAS AF = 0.045 (232/5158). AF 95% confidence interval is 0.0402. There are 82 homozygotes in GnomAd4. There are 2273 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 82 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.3162G>A	p.Pro1054Pro	synonymous	Exon 24 of 25	NP_001243474.1
	MEGF10	NM_032446.3		c.3162G>A	p.Pro1054Pro	synonymous	Exon 25 of 26	NP_115822.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.3162G>A	p.Pro1054Pro	synonymous	Exon 24 of 25	ENSP00000423354.2
	MEGF10	ENST00000274473.6	TSL:1	c.3162G>A	p.Pro1054Pro	synonymous	Exon 25 of 26	ENSP00000274473.6
	MEGF10	ENST00000510828.5	TSL:5	n.661G>A		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4925 AN: 152020 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.0410

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.0449

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0192

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0326

GnomAD2 exomes AF: 0.0277 AC: 6946 AN: 251148 AF XY: 0.0272

Gnomad AFR exome AF: 0.0381

Gnomad AMR exome AF: 0.0207

Gnomad ASJ exome AF: 0.0203

Gnomad EAS exome AF: 0.0449

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0276

GnomAD4 exome AF: 0.0319 AC: 46669 AN: 1461714 Hom.: 832 Cov.: 31 AF XY: 0.0312 AC XY: 22721 AN XY: 727158

African (AFR) AF: 0.0395 AC: 1323 AN: 33476

American (AMR) AF: 0.0210 AC: 941 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 432 AN: 26132

East Asian (EAS) AF: 0.0373 AC: 1479 AN: 39682

South Asian (SAS) AF: 0.0138 AC: 1188 AN: 86246

European-Finnish (FIN) AF: 0.0224 AC: 1199 AN: 53412

Middle Eastern (MID) AF: 0.0330 AC: 190 AN: 5766

European-Non Finnish (NFE) AF: 0.0340 AC: 37780 AN: 1111892

Other (OTH) AF: 0.0354 AC: 2137 AN: 60386

GnomAD4 genome AF: 0.0324 AC: 4932 AN: 152138 Hom.: 82 Cov.: 32 AF XY: 0.0306 AC XY: 2273 AN XY: 74366

African (AFR) AF: 0.0412 AC: 1708 AN: 41502

American (AMR) AF: 0.0271 AC: 414 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3468

East Asian (EAS) AF: 0.0450 AC: 232 AN: 5158

South Asian (SAS) AF: 0.0125 AC: 60 AN: 4818

European-Finnish (FIN) AF: 0.0192 AC: 203 AN: 10596

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0319 AC: 2171 AN: 68008

Other (OTH) AF: 0.0318 AC: 67 AN: 2110

Alfa AF: 0.0297 Hom.: 145

Bravo AF: 0.0343

Asia WGS AF: 0.0280 AC: 97 AN: 3478

EpiCase AF: 0.0313

EpiControl AF: 0.0290

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jan 28, 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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MEGF10-related myopathy Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.78
DANN	Benign	0.54
PhyloP100		-3.5
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: rs17164938; hg19: chr5-126791229; COSMIC: COSV57246317;