rs145815113

Positions:

• chr5-127410479-C-A
• chr5-127410479-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000503335.7(MEGF10):​c.1008C>A​(p.Ser336Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S336N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MEGF10 ENST00000503335.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEGF10	NM_001256545.2	c.1008C>A	p.Ser336Arg	missense_variant	9/25	ENST00000503335.7	NP_001243474.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEGF10	ENST00000503335.7	c.1008C>A	p.Ser336Arg	missense_variant	9/25	1	NM_001256545.2	ENSP00000423354	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	0.070
DANN	Benign	0.93
DEOGEN2	Benign	0.046	T;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.15	N
LIST_S2	Uncertain	0.86	.;.;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.8	M;M;M;M
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		0.79	P;P;P;P
Vest4		0.65
MutPred		0.67		Loss of glycosylation at S336 (P = 0.0196);Loss of glycosylation at S336 (P = 0.0196);Loss of glycosylation at S336 (P = 0.0196);Loss of glycosylation at S336 (P = 0.0196);
MVP		0.33
MPC		0.25
ClinPred		0.88	D
GERP RS		-8.1
Varity_R		0.32
gMVP		0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs145815113; hg19: chr5-126746171; COSMIC: COSV57246014;