5-127454588-C-G

Variant names:

• chr5-127454588-C-G
• rs35159176
• NM_001256545.2:c.3003C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001256545.2(MEGF10):​c.3003C>G​(p.Ser1001Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S1001S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: MEGF10 NM_001256545.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.440
• Publications: 2 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.3003C>G	p.Ser1001Arg	missense	Exon 23 of 25	NP_001243474.1	Q96KG7-1
	MEGF10	NM_032446.3		c.3003C>G	p.Ser1001Arg	missense	Exon 24 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.3003C>G	p.Ser1001Arg	missense	Exon 23 of 25	ENSP00000423354.2	Q96KG7-1
	MEGF10	ENST00000274473.6	TSL:1	c.3003C>G	p.Ser1001Arg	missense	Exon 24 of 26	ENSP00000274473.6	Q96KG7-1
	MEGF10	ENST00000510828.5	TSL:5	n.502C>G		non_coding_transcript_exon	Exon 5 of 6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245676 AF XY: 0.00000752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1455568 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 723896

African (AFR) AF: 0.00 AC: 0 AN: 33084

American (AMR) AF: 0.00 AC: 0 AN: 43804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25954

East Asian (EAS) AF: 0.00 AC: 0 AN: 39484

South Asian (SAS) AF: 0.00 AC: 0 AN: 84546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1109616

Other (OTH) AF: 0.00 AC: 0 AN: 60092

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000103 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	MEGF10-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.81
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.44
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.17
Sift	Benign	0.92	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.31
MutPred		0.40		Gain of MoRF binding (P = 0.0186)
MVP		0.15
MPC		0.25
ClinPred		0.11	T
GERP RS		1.4
Varity_R		0.033
gMVP		0.44
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.59		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.59		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35159176; hg19: chr5-126790280;