NM_001256545.2:c.2757C>A

Variant names:

• chr5-127447585-C-A
• NM_001256545.2:c.2757C>A
• MEGF10 p.Asn919Lys

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001256545.2(MEGF10):​c.2757C>A​(p.Asn919Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N919N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131
• 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, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39494264).

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.2757C>A	p.Asn919Lys	missense	Exon 21 of 25	NP_001243474.1	Q96KG7-1
	MEGF10	NM_032446.3		c.2757C>A	p.Asn919Lys	missense	Exon 22 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.2757C>A	p.Asn919Lys	missense	Exon 21 of 25	ENSP00000423354.2	Q96KG7-1
	MEGF10	ENST00000274473.6	TSL:1	c.2757C>A	p.Asn919Lys	missense	Exon 22 of 26	ENSP00000274473.6	Q96KG7-1
	MEGF10	ENST00000507158.1	TSL:2	n.246C>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.13
DANN	Benign	0.59
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.13
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.18
Sift	Benign	0.096	T
Sift4G	Benign	0.73	T
Varity_R		0.032
gMVP		0.39
Mutation Taster		=83/17	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-126783277;