rs748227745

Variant names:

• chr5-127419194-T-G
• rs748227745
• NM_001256545.2:c.1380T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001256545.2(MEGF10):​c.1380T>G​(p.Asn460Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -2.02
• Publications: 0 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1380T>G	p.Asn460Lys	missense	Exon 11 of 25	NP_001243474.1	Q96KG7-1
	MEGF10	NM_032446.3		c.1380T>G	p.Asn460Lys	missense	Exon 12 of 26	NP_115822.1	Q96KG7-1
	MEGF10	NM_001308119.2		c.1380T>G	p.Asn460Lys	missense	Exon 12 of 15	NP_001295048.1	Q96KG7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEGF10	ENST00000503335.7	TSL:1 MANE Select	c.1380T>G	p.Asn460Lys	missense	Exon 11 of 25	ENSP00000423354.2	Q96KG7-1
	MEGF10	ENST00000274473.6	TSL:1	c.1380T>G	p.Asn460Lys	missense	Exon 12 of 26	ENSP00000274473.6	Q96KG7-1
	MEGF10	ENST00000418761.6	TSL:1	c.1380T>G	p.Asn460Lys	missense	Exon 12 of 15	ENSP00000416284.2	Q96KG7-2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251442 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1112004

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	MEGF10-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.5
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.9	H
PhyloP100		-2.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.74	P
Vest4		0.94
MutPred		0.46		Gain of ubiquitination at N460 (P = 0.009)
MVP		0.28
MPC		0.64
ClinPred		0.84	D
GERP RS		-7.8
Varity_R		0.79
gMVP		0.78
Mutation Taster		=27/73	disease causing

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: rs748227745; hg19: chr5-126754886;