6-35228616-G-A

Position:

• chr6-35228616-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_152753.4(SCUBE3):​c.211G>A​(p.Val71Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000342 in 1,461,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SCUBE3 NM_152753.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.59

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.36437356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCUBE3	NM_152753.4	c.211G>A	p.Val71Met	missense_variant, splice_region_variant	3/22	ENST00000274938.8	NP_689966.2
SCUBE3-AS1	XR_001744102.2	n.3185C>T		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCUBE3	ENST00000274938.8	c.211G>A	p.Val71Met	missense_variant, splice_region_variant	3/22	1	NM_152753.4	ENSP00000274938	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250894 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135568

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461592 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Oct 10, 2023

The c.211G>A (p.V71M) alteration is located in exon 3 (coding exon 3) of the SCUBE3 gene. This alteration results from a G to A substitution at nucleotide position 211, causing the valine (V) at amino acid position 71 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	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.56
Sift	Benign	0.067	T
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.44
MutPred		0.35		Gain of ubiquitination at K66 (P = 0.0938);
MVP		0.78
MPC		0.85
ClinPred		0.59	D
GERP RS		5.3
Varity_R		0.19
gMVP		0.79

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: rs765067484; hg19: chr6-35196393;