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GeneBe

6-35228696-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PP2PP3_StrongPP5_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

Scores

15
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.33
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, SCUBE3
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 id is 981655.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SCUBE3NM_152753.4 linkuse as main transcriptc.291C>G p.Cys97Trp missense_variant 3/22 ENST00000274938.8
SCUBE3-AS1XR_001744102.2 linkuse as main transcriptn.3105G>C non_coding_transcript_exon_variant 4/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SCUBE3ENST00000274938.8 linkuse as main transcriptc.291C>G p.Cys97Trp missense_variant 3/221 NM_152753.4 P1Q8IX30-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMFeb 15, 2021- -
Abnormality of the dentition;C0349588:Short stature;C0424503:Abnormal facial shape;C4021790:Abnormality of the skeletal system Pathogenic:1
Pathogenic, criteria provided, single submitterresearchTartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's HospitalSep 01, 2020- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster
Benign
1.0
D;D
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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1783419625; hg19: chr6-35196473; API