chr6-35239766-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BS1_Supporting
The NM_152753.4(SCUBE3):c.844C>T(p.Arg282Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00029 in 1,611,552 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00029 ( 0 hom. )
Consequence
SCUBE3
NM_152753.4 missense
NM_152753.4 missense
Scores
7
10
2
Clinical Significance
Conservation
PhyloP100: 4.03
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 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
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000296 (45/152154) while in subpopulation AMR AF= 0.0017 (26/15278). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCUBE3 | NM_152753.4 | c.844C>T | p.Arg282Cys | missense_variant | 8/22 | ENST00000274938.8 | |
SCUBE3-AS1 | XR_001744102.2 | n.320+4582G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCUBE3 | ENST00000274938.8 | c.844C>T | p.Arg282Cys | missense_variant | 8/22 | 1 | NM_152753.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000296 AC: 45AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000221 AC: 55AN: 248678Hom.: 0 AF XY: 0.000201 AC XY: 27AN XY: 134448
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GnomAD4 exome AF: 0.000290 AC: 423AN: 1459398Hom.: 0 Cov.: 30 AF XY: 0.000267 AC XY: 194AN XY: 725986
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 17, 2022 | The c.844C>T (p.R282C) alteration is located in exon 8 (coding exon 8) of the SCUBE3 gene. This alteration results from a C to T substitution at nucleotide position 844, causing the arginine (R) at amino acid position 282 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Uncertain
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at