6-35233221-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP3 BS1_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

SCUBE3-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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, 0.773
• 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	UniProt
SCUBE3	NM_152753.4	c.632C>T	p.Thr211Met	missense_variant	6/22	ENST00000274938.8
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	Appris	UniProt
SCUBE3	ENST00000274938.8	c.632C>T	p.Thr211Met	missense_variant	6/22	1	NM_152753.4	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152058 Hom.: 0 Cov.: 31

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

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

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

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

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: 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

Other links and lift over

dbSNP: rs369592922; hg19: chr6-35200998;