6-35233221-C-T

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

Scores

3
10
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.81
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]

Genome browser will be placed here

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
SCUBE3NM_152753.4 linkuse as main transcriptc.632C>T p.Thr211Met missense_variant 6/22 ENST00000274938.8 NP_689966.2
SCUBE3-AS1XR_001744102.2 linkuse as main transcriptn.321-1741G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SCUBE3ENST00000274938.8 linkuse as main transcriptc.632C>T p.Thr211Met missense_variant 6/221 NM_152753.4 ENSP00000274938 P1Q8IX30-1

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152058
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000235
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000144
AC:
36
AN:
250642
Hom.:
0
AF XY:
0.000155
AC XY:
21
AN XY:
135588
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.0000463
Gnomad NFE exome
AF:
0.000283
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000205
AC:
299
AN:
1461582
Hom.:
0
Cov.:
31
AF XY:
0.000186
AC XY:
135
AN XY:
727110
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.000256
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152058
Hom.:
0
Cov.:
31
AF XY:
0.000175
AC XY:
13
AN XY:
74266
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.000235
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000213
Hom.:
0
Bravo
AF:
0.000162
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000173
AC:
21
EpiCase
AF:
0.000382
EpiControl
AF:
0.000119

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 submitterclinical testingAmbry GeneticsDec 14, 2021The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.093
BayesDel_addAF
Benign
-0.053
T
BayesDel_noAF
Uncertain
-0.010
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.49
T
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.77
D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Benign
1.6
L
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-2.1
N
REVEL
Uncertain
0.48
Sift
Benign
0.081
T
Sift4G
Uncertain
0.016
D
Polyphen
0.97
D
Vest4
0.54
MVP
0.72
MPC
1.7
ClinPred
0.40
T
GERP RS
5.3
Varity_R
0.10
gMVP
0.74

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs369592922; hg19: chr6-35200998; API