22-43208158-G-A

Variant names:

• chr22-43208158-G-A
• NM_173050.5:c.2648C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_173050.5(SCUBE1):​c.2648C>T​(p.Ser883Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCUBE1 NM_173050.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.87
• Publications: 0 publications found

Genes affected

SCUBE1 (HGNC:13441): (signal peptide, CUB domain and EGF like domain containing 1) This gene encodes a cell surface glycoprotein that is a member of the SCUBE (signal peptide, CUB domain, EGF (epidermal growth factor)-like protein) family. Family members have an amino-terminal signal peptide, nine copies of EGF-like repeats and a CUB domain at the carboxyl terminus. This protein is expressed in platelets and endothelial cells and may play an important role in vascular biology. [provided by RefSeq, Oct 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173050.5. 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
	SCUBE1	NM_173050.5	MANE Select	c.2648C>T	p.Ser883Phe	missense	Exon 20 of 22	NP_766638.2	Q8IWY4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCUBE1	ENST00000360835.9	TSL:1 MANE Select	c.2648C>T	p.Ser883Phe	missense	Exon 20 of 22	ENSP00000354080.3	Q8IWY4
	SCUBE1	ENST00000911327.1		c.2585C>T	p.Ser862Phe	missense	Exon 20 of 22	ENSP00000581386.1
	SCUBE1	ENST00000911329.1		c.2585C>T	p.Ser862Phe	missense	Exon 20 of 22	ENSP00000581388.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.092	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.80		Loss of catalytic residue at S883 (P = 0.0476)
MVP		0.73
MPC		1.7
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.65
gMVP		0.80
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr22-43604164;