5-127435419-C-T

Variant names:

• chr5-127435419-C-T
• rs117124929
• NM_001256545.2:c.2034C>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.2034C>T​(p.Asn678Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,614,078 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (30 hom.)
• Consequence: MEGF10 NM_001256545.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.905
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 5-127435419-C-T is Benign according to our data. Variant chr5-127435419-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.905 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00194 (295/152304) while in subpopulation EAS AF = 0.0417 (216/5184). AF 95% confidence interval is 0.0371. There are 5 homozygotes in GnomAd4. There are 160 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.2034C>T	p.Asn678Asn	synonymous	Exon 16 of 25	NP_001243474.1
	MEGF10	NM_032446.3		c.2034C>T	p.Asn678Asn	synonymous	Exon 17 of 26	NP_115822.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.2034C>T	p.Asn678Asn	synonymous	Exon 16 of 25	ENSP00000423354.2
	MEGF10	ENST00000274473.6	TSL:1	c.2034C>T	p.Asn678Asn	synonymous	Exon 17 of 26	ENSP00000274473.6
	MEGF10	ENST00000506709.1	TSL:3	n.275C>T		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 296 AN: 152186 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0416

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00341 AC: 856 AN: 251340 AF XY: 0.00327

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0419

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00128 AC: 1870 AN: 1461774 Hom.: 30 Cov.: 30 AF XY: 0.00125 AC XY: 911 AN XY: 727182

African (AFR) AF: 0.000717 AC: 24 AN: 33478

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0334 AC: 1326 AN: 39686

South Asian (SAS) AF: 0.00159 AC: 137 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000908 AC: 101 AN: 1111956

Other (OTH) AF: 0.00452 AC: 273 AN: 60382

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152304 Hom.: 5 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74474

African (AFR) AF: 0.00123 AC: 51 AN: 41562

American (AMR) AF: 0.000458 AC: 7 AN: 15300

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

East Asian (EAS) AF: 0.0417 AC: 216 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000332 Hom.: 0

Bravo AF: 0.00228

Asia WGS AF: 0.0150 AC: 51 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

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	-0.30
CADD	Benign	1.1
DANN	Benign	0.67
PhyloP100		-0.91
Mutation Taster		=87/13	polymorphism

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: rs117124929; hg19: chr5-126771111;