NM_152753.4:c.59C>T

Variant names:

• chr6-35214477-C-T
• rs1782807002
• NM_152753.4:c.59C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152753.4(SCUBE3):​c.59C>T​(p.Ala20Val) 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SCUBE3 NM_152753.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.562
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Ambry Genetics

ENSG00000305352 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16126752).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152753.4. 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
	SCUBE3	NM_152753.4	MANE Select	c.59C>T	p.Ala20Val	missense	Exon 1 of 22	NP_689966.2
	SCUBE3	NM_001303136.2		c.59C>T	p.Ala20Val	missense	Exon 1 of 22	NP_001290065.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCUBE3	ENST00000274938.8	TSL:1 MANE Select	c.59C>T	p.Ala20Val	missense	Exon 1 of 22	ENSP00000274938.7	Q8IX30-1
	SCUBE3	ENST00000889524.1		c.59C>T	p.Ala20Val	missense	Exon 1 of 23	ENSP00000559583.1
	SCUBE3	ENST00000940915.1		c.59C>T	p.Ala20Val	missense	Exon 1 of 23	ENSP00000610974.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1353250 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 669810

African (AFR) AF: 0.00 AC: 0 AN: 28444

American (AMR) AF: 0.00 AC: 0 AN: 31200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23890

East Asian (EAS) AF: 0.00 AC: 0 AN: 30730

South Asian (SAS) AF: 0.00 AC: 0 AN: 75106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4210

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1063268

Other (OTH) AF: 0.00 AC: 0 AN: 55874

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.56
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.16
Sift	Benign	0.34	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.52		Loss of disorder (P = 0.0905)
MVP		0.28
MPC		0.81
ClinPred		0.22	T
GERP RS		3.3
Varity_R		0.056
gMVP		0.40
Mutation Taster		=95/5	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

Other links and lift over

dbSNP: rs1782807002; hg19: chr6-35182254; COSMIC: COSV107289039;