6-35233280-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_152753.4(SCUBE3):c.691A>G(p.Thr231Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.009 in 1,608,246 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0092 (125 hom.)
• Consequence: SCUBE3 NM_152753.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.63

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 Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SCUBE3
• BP4: Computational evidence support a benign effect (MetaRNN=0.010085374).
• BP6: Variant 6-35233280-A-G is Benign according to our data. Variant chr6-35233280-A-G is described in ClinVar as [Benign]. Clinvar id is 708924.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00721 (1091/151336) while in subpopulation EAS AF= 0.0143 (73/5122). AF 95% confidence interval is 0.0116. There are 4 homozygotes in gnomad4. There are 554 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCUBE3	NM_152753.4	c.691A>G	p.Thr231Ala	missense_variant	6/22	ENST00000274938.8
SCUBE3-AS1	XR_001744102.2	n.321-1800T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCUBE3	ENST00000274938.8	c.691A>G	p.Thr231Ala	missense_variant	6/22	1	NM_152753.4	P1

Frequencies

GnomAD3 genomes AF: 0.00721 AC: 1091 AN: 151218 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00185

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.0140

Gnomad SAS AF: 0.0107

Gnomad FIN AF: 0.00343

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00919

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00868 AC: 2179 AN: 251146 Hom.: 14 AF XY: 0.00956 AC XY: 1298 AN XY: 135738

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00686

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.00707

Gnomad SAS exome AF: 0.0129

Gnomad FIN exome AF: 0.00319

Gnomad NFE exome AF: 0.00992

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00919 AC: 13391 AN: 1456910 Hom.: 125 Cov.: 30 AF XY: 0.00939 AC XY: 6810 AN XY: 725018

Gnomad4 AFR exome AF: 0.00174

Gnomad4 AMR exome AF: 0.00739

Gnomad4 ASJ exome AF: 0.0135

Gnomad4 EAS exome AF: 0.0347

Gnomad4 SAS exome AF: 0.0132

Gnomad4 FIN exome AF: 0.00385

Gnomad4 NFE exome AF: 0.00830

Gnomad4 OTH exome AF: 0.00941

GnomAD4 genome AF: 0.00721 AC: 1091 AN: 151336 Hom.: 4 Cov.: 31 AF XY: 0.00749 AC XY: 554 AN XY: 73940

Gnomad4 AFR AF: 0.00184

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.0105

Gnomad4 FIN AF: 0.00343

Gnomad4 NFE AF: 0.00919

Gnomad4 OTH AF: 0.0143

Alfa AF: 0.00936 Hom.: 17

Bravo AF: 0.00694

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00942 AC: 81

ExAC AF: 0.00894 AC: 1086

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0121

EpiControl AF: 0.0127

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	20
Dann	Benign	0.94
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.21	N
MutationTaster	Benign	0.91	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.17
Sift	Benign	0.37	T
Sift4G	Benign	0.43	T
Polyphen		0.083	B
Vest4		0.23
MVP		0.81
MPC		0.77
ClinPred		0.020	T
GERP RS		4.6
Varity_R		0.092
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs79753406; hg19: chr6-35201057; COSMIC: COSV51457121;