6-35237988-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_152753.4(SCUBE3):c.799A>C(p.Met267Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SCUBE3 NM_152753.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52

Genes affected

SCUBE3 (HGNC:13655): (signal peptide, CUB domain and EGF like domain containing 3) This gene encodes a member of the signal peptide, complement subcomponents C1r/C1s, Uegf, bone morphogenetic protein-1 and epidermal growth factor-like domain containing protein family. Overexpression of this gene in human embryonic kidney cells results in secretion of a glycosylated form of the protein that forms oligomers and tethers to the cell surface. This gene is upregulated in lung cancer tumor tissue compared to healthy tissue and is associated with loss of the epithelial marker E-cadherin and with increased expression of vimentin, a mesenchymal marker. In addition, the protein encoded by this gene is a transforming growth factor beta receptor ligand, and when secreted by cancer cells, it can be cleaved in vitro to release the N-terminal epidermal growth factor-like repeat domain and the C-terminal complement subcomponents C1r/C1s domain. Both the full length protein and C-terminal fragment can bind to the transforming growth factor beta type II receptor to promote the epithelial-mesenchymal transition and tumor angiogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

SCUBE3-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SCUBE3
• BP4: Computational evidence support a benign effect (MetaRNN=0.34686148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCUBE3	NM_152753.4	c.799A>C	p.Met267Leu	missense_variant	7/22	ENST00000274938.8
SCUBE3-AS1	XR_001744102.2	n.320+6360T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCUBE3	ENST00000274938.8	c.799A>C	p.Met267Leu	missense_variant	7/22	1	NM_152753.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457432 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense c.799A>C(p.Met267Leu) variant in SCUBE3 has not been reported as a pathogenic variant nor a benign variant, to our knowledge. The p.Met267Leu variant is novel (not in any individuals) in both gnomAD Exomes and 1000 Genomes databases. This variant has not been reported to the ClinVar database. The amino acid change p.Met267Leu in SCUBE3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 267 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	24
Dann	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.060
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	-0.59	N
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.59	N
REVEL	Uncertain	0.41
Sift	Benign	0.043	D
Sift4G	Uncertain	0.028	D
Polyphen		0.065	B
Vest4		0.39
MutPred		0.56		Gain of catalytic residue at M267 (P = 0.0067);
MVP		0.82
MPC		0.79
ClinPred		0.92	D
GERP RS		3.9
Varity_R		0.26
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-35205765;