6-35233280-A-G

Position:

chr6-35233280-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.63

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]

SCUBE3 links:

SCUBE3-AS1 (HGNC:):

SCUBE3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

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.

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 GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCUBE3	NM_152753.4 linkuse as main transcript	c.691A>G	p.Thr231Ala	missense_variant	6/22	ENST00000274938.8	NP_689966.2
SCUBE3-AS1	XR_001744102.2 linkuse as main transcript	n.321-1800T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCUBE3	ENST00000274938.8 linkuse as main transcript	c.691A>G	p.Thr231Ala	missense_variant	6/22	1	NM_152753.4	ENSP00000274938	P1	Q8IX30-1

Frequencies

GnomAD3 genomes

AF:

0.00721

AC:

1091

AN:

151218

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00956

AC XY:

1298

AN XY:

135738

show subpopulations

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.:

AF XY:

0.00939

AC XY:

6810

AN XY:

725018

show subpopulations

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.:

Cov.:

AF XY:

0.00749

AC XY:

554

AN XY:

73940

show subpopulations

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.:

Bravo

AF:

0.00694

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00942

AC:

ExAC

AF:

0.00894

AC:

1086

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0121

EpiControl

AF:

0.0127

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 03, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.063

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.28

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.50

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.21

MutationTaster

Benign

0.91

N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.97

REVEL

Benign

0.17

Sift

Benign

0.37

Sift4G

Benign

0.43

Polyphen

0.083

Vest4

0.23

MVP

0.81

MPC

0.77

ClinPred

0.020

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over