rs1783419625

Variant names:

• chr6-35228696-C-G
• rs1783419625
• NM_152753.4:c.291C>G

Your query was ambiguous. Multiple possible variants found:

• chr6-35228696-C-G
• chr6-35228696-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_152753.4(SCUBE3):​c.291C>G​(p.Cys97Trp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCUBE3 NM_152753.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.33
• Publications: 2 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-AS1 (HGNC:56671): (SCUBE3 antisense RNA 1)

ENSG00000305352 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 6-35228696-C-G is Pathogenic according to our data. Variant chr6-35228696-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 981655.Status of the report is criteria_provided_single_submitter, 1 stars.

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.291C>G	p.Cys97Trp	missense	Exon 3 of 22	NP_689966.2
	SCUBE3	NM_001303136.2		c.291C>G	p.Cys97Trp	missense	Exon 3 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.291C>G	p.Cys97Trp	missense	Exon 3 of 22	ENSP00000274938.7	Q8IX30-1
	SCUBE3	ENST00000889524.1		c.291C>G	p.Cys97Trp	missense	Exon 3 of 23	ENSP00000559583.1
	SCUBE3	ENST00000940915.1		c.291C>G	p.Cys97Trp	missense	Exon 3 of 23	ENSP00000610974.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Abnormality of the dentition;C0349588:Short stature;C0424503:Abnormal facial shape;C4021790:Abnormality of the skeletal system (1)
1	-	-	Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		1.3
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.2	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.94		Loss of catalytic residue at T96 (P = 0.118)
MVP		0.95
MPC		2.2
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.93
gMVP		1.0
Mutation Taster		=28/72	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1783419625; hg19: chr6-35196473;