6-35233221-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP2PP3BS1_Supporting
The NM_152753.4(SCUBE3):c.632C>T(p.Thr211Met) variant causes a missense change. The variant allele was found at a frequency of 0.0002 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00015 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00020 ( 0 hom. )
Consequence
SCUBE3
NM_152753.4 missense
NM_152753.4 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 4.81
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 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCUBE3. . Gene score misZ 2.6996 (greater than the threshold 3.09). Trascript score misZ 3.1823 (greater than threshold 3.09). GenCC has associacion of gene with short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 2.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.773
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000205 (299/1461582) while in subpopulation NFE AF= 0.000256 (285/1111774). AF 95% confidence interval is 0.000231. There are 0 homozygotes in gnomad4_exome. There are 135 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCUBE3 | NM_152753.4 | c.632C>T | p.Thr211Met | missense_variant | 6/22 | ENST00000274938.8 | NP_689966.2 | |
SCUBE3-AS1 | XR_001744102.2 | n.321-1741G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SCUBE3 | ENST00000274938.8 | c.632C>T | p.Thr211Met | missense_variant | 6/22 | 1 | NM_152753.4 | ENSP00000274938 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152058Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000144 AC: 36AN: 250642Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135588
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GnomAD4 exome AF: 0.000205 AC: 299AN: 1461582Hom.: 0 Cov.: 31 AF XY: 0.000186 AC XY: 135AN XY: 727110
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GnomAD4 genome AF: 0.000151 AC: 23AN: 152058Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13AN XY: 74266
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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 | Dec 14, 2021 | The c.632C>T (p.T211M) alteration is located in exon 6 (coding exon 6) of the SCUBE3 gene. This alteration results from a C to T substitution at nucleotide position 632, causing the threonine (T) at amino acid position 211 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
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gMVP
Splicing
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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