5-127438533-C-T

Variant names:

• chr5-127438533-C-T
• rs35591368
• NM_001256545.2:c.2199C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001256545.2(MEGF10):​c.2199C>T​(p.Cys733Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0308 in 1,614,016 control chromosomes in the GnomAD database, including 854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (49 hom., cov: 32)
  • Exomes 𝑓: 0.031 (805 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.287
• Publications: 7 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=-0.43).
• BP6: Variant 5-127438533-C-T is Benign according to our data. Variant chr5-127438533-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.287 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.026 (3963/152294) while in subpopulation EAS AF = 0.045 (233/5180). AF 95% confidence interval is 0.0402. There are 49 homozygotes in GnomAd4. There are 1829 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	NM_001256545.2	MANE Select	c.2199C>T	p.Cys733Cys	synonymous	Exon 17 of 25	NP_001243474.1	Q96KG7-1
	MEGF10	NM_032446.3		c.2199C>T	p.Cys733Cys	synonymous	Exon 18 of 26	NP_115822.1	Q96KG7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.2199C>T	p.Cys733Cys	synonymous	Exon 17 of 25	ENSP00000423354.2	Q96KG7-1
	MEGF10	ENST00000274473.6	TSL:1	c.2199C>T	p.Cys733Cys	synonymous	Exon 18 of 26	ENSP00000274473.6	Q96KG7-1
	MEGF10	ENST00000506709.1	TSL:3	n.440C>T		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 3963 AN: 152176 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0449

Gnomad SAS AF: 0.0129

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0278

GnomAD2 exomes AF: 0.0261 AC: 6501 AN: 249522 AF XY: 0.0259

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.0198

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.0449

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0260

GnomAD4 exome AF: 0.0312 AC: 45678 AN: 1461722 Hom.: 805 Cov.: 31 AF XY: 0.0307 AC XY: 22307 AN XY: 727168

African (AFR) AF: 0.0167 AC: 558 AN: 33480

American (AMR) AF: 0.0198 AC: 887 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 404 AN: 26134

East Asian (EAS) AF: 0.0372 AC: 1478 AN: 39696

South Asian (SAS) AF: 0.0134 AC: 1159 AN: 86258

European-Finnish (FIN) AF: 0.0224 AC: 1198 AN: 53406

Middle Eastern (MID) AF: 0.0280 AC: 161 AN: 5754

European-Non Finnish (NFE) AF: 0.0340 AC: 37797 AN: 1111882

Other (OTH) AF: 0.0337 AC: 2036 AN: 60390

GnomAD4 genome AF: 0.0260 AC: 3963 AN: 152294 Hom.: 49 Cov.: 32 AF XY: 0.0246 AC XY: 1829 AN XY: 74458

African (AFR) AF: 0.0187 AC: 779 AN: 41560

American (AMR) AF: 0.0253 AC: 387 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.0450 AC: 233 AN: 5180

South Asian (SAS) AF: 0.0129 AC: 62 AN: 4818

European-Finnish (FIN) AF: 0.0190 AC: 202 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0320 AC: 2176 AN: 68036

Other (OTH) AF: 0.0270 AC: 57 AN: 2112

Alfa AF: 0.0276 Hom.: 58

Bravo AF: 0.0268

Asia WGS AF: 0.0260 AC: 91 AN: 3478

EpiCase AF: 0.0310

EpiControl AF: 0.0289

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.9
DANN	Benign	0.48
PhyloP100		0.29
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs35591368; hg19: chr5-126774225; COSMIC: COSV108037271;