NM_001256545.2:c.116+10T>C

Variant names:

• chr5-127331434-T-C
• rs10519949
• NM_001256545.2:c.116+10T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256545.2(MEGF10):​c.116+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 1,516,882 control chromosomes in the GnomAD database, including 917 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (128 hom., cov: 32)
  • Exomes 𝑓: 0.022 (789 hom.)
• Consequence: MEGF10 NM_001256545.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.716
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 5-127331434-T-C is Benign according to our data. Variant chr5-127331434-T-C is described in ClinVar as Benign. ClinVar VariationId is 262061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

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.116+10T>C		intron	N/A	NP_001243474.1
	MEGF10	NM_032446.3		c.116+10T>C		intron	N/A	NP_115822.1
	MEGF10	NM_001308119.2		c.116+10T>C		intron	N/A	NP_001295048.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.116+10T>C		intron	N/A	ENSP00000423354.2
	MEGF10	ENST00000274473.6	TSL:1	c.116+10T>C		intron	N/A	ENSP00000274473.6
	MEGF10	ENST00000418761.6	TSL:1	c.116+10T>C		intron	N/A	ENSP00000416284.2

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4600 AN: 152130 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.0522

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.0913

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0273

GnomAD2 exomes AF: 0.0333 AC: 8121 AN: 243834 AF XY: 0.0351

Gnomad AFR exome AF: 0.0473

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.0512

Gnomad EAS exome AF: 0.109

Gnomad FIN exome AF: 0.0166

Gnomad NFE exome AF: 0.0135

Gnomad OTH exome AF: 0.0288

GnomAD4 exome AF: 0.0216 AC: 29420 AN: 1364634 Hom.: 789 Cov.: 21 AF XY: 0.0233 AC XY: 15932 AN XY: 683978

African (AFR) AF: 0.0510 AC: 1597 AN: 31304

American (AMR) AF: 0.0125 AC: 536 AN: 42964

Ashkenazi Jewish (ASJ) AF: 0.0494 AC: 1246 AN: 25234

East Asian (EAS) AF: 0.112 AC: 4378 AN: 39174

South Asian (SAS) AF: 0.0825 AC: 6794 AN: 82382

European-Finnish (FIN) AF: 0.0165 AC: 879 AN: 53266

Middle Eastern (MID) AF: 0.0346 AC: 193 AN: 5574

European-Non Finnish (NFE) AF: 0.0119 AC: 12220 AN: 1027594

Other (OTH) AF: 0.0276 AC: 1577 AN: 57142

GnomAD4 genome AF: 0.0302 AC: 4605 AN: 152248 Hom.: 128 Cov.: 32 AF XY: 0.0318 AC XY: 2370 AN XY: 74436

African (AFR) AF: 0.0483 AC: 2005 AN: 41540

American (AMR) AF: 0.0151 AC: 231 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0522 AC: 181 AN: 3470

East Asian (EAS) AF: 0.112 AC: 580 AN: 5182

South Asian (SAS) AF: 0.0911 AC: 440 AN: 4828

European-Finnish (FIN) AF: 0.0195 AC: 207 AN: 10616

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 855 AN: 68012

Other (OTH) AF: 0.0275 AC: 58 AN: 2112

Alfa AF: 0.0193 Hom.: 62

Bravo AF: 0.0294

Asia WGS AF: 0.0850 AC: 297 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	MEGF10-related myopathy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.1
DANN	Benign	0.82
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs10519949; hg19: chr5-126667126; COSMIC: COSV57246306;