chr6-35233280-A-G

Variant names:

• chr6-35233280-A-G
• rs79753406
• NM_152753.4:c.691A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. 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. 15/21 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
• Publications: 10 publications found

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]

ENSG00000305352 (HGNC:):

SCUBE3-AS1 (HGNC:56671): (SCUBE3 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• 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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152753.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCUBE3	NM_152753.4	MANE Select	c.691A>G	p.Thr231Ala	missense	Exon 6 of 22	NP_689966.2
	SCUBE3	NM_001303136.2		c.688A>G	p.Thr230Ala	missense	Exon 6 of 22	NP_001290065.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCUBE3	ENST00000274938.8	TSL:1 MANE Select	c.691A>G	p.Thr231Ala	missense	Exon 6 of 22	ENSP00000274938.7	Q8IX30-1
	SCUBE3	ENST00000889524.1		c.691A>G	p.Thr231Ala	missense	Exon 6 of 23	ENSP00000559583.1
	SCUBE3	ENST00000940915.1		c.688A>G	p.Thr230Ala	missense	Exon 6 of 23	ENSP00000610974.1

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

GnomAD2 exomes AF: 0.00868 AC: 2179 AN: 251146 AF XY: 0.00956

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 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

African (AFR) AF: 0.00174 AC: 58 AN: 33336

American (AMR) AF: 0.00739 AC: 330 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 351 AN: 26042

East Asian (EAS) AF: 0.0347 AC: 1371 AN: 39552

South Asian (SAS) AF: 0.0132 AC: 1140 AN: 86178

European-Finnish (FIN) AF: 0.00385 AC: 205 AN: 53222

Middle Eastern (MID) AF: 0.0294 AC: 169 AN: 5748

European-Non Finnish (NFE) AF: 0.00830 AC: 9201 AN: 1108008

Other (OTH) AF: 0.00941 AC: 566 AN: 60170

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

African (AFR) AF: 0.00184 AC: 76 AN: 41198

American (AMR) AF: 0.0104 AC: 159 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3464

East Asian (EAS) AF: 0.0143 AC: 73 AN: 5122

South Asian (SAS) AF: 0.0105 AC: 50 AN: 4746

European-Finnish (FIN) AF: 0.00343 AC: 36 AN: 10488

Middle Eastern (MID) AF: 0.0240 AC: 7 AN: 292

European-Non Finnish (NFE) AF: 0.00919 AC: 623 AN: 67780

Other (OTH) AF: 0.0143 AC: 30 AN: 2104

Alfa AF: 0.00933 Hom.: 39

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.6
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
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs79753406; hg19: chr6-35201057; COSMIC: COSV51457121;