4-67571120-A-C

Position:

• chr4-67571120-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012108.4(STAP1):​c.157A>C​(p.Thr53Pro) variant causes a missense change. 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: 32)
• Consequence: STAP1 NM_012108.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78

Genes affected

STAP1 (HGNC:24133): (signal transducing adaptor family member 1) The protein encoded by this gene contains a proline-rich region, a pleckstrin homology (PH) domain, and a region in the carboxy terminal half with similarity to the Src Homology 2 (SH2) domain. This protein is a substrate of tyrosine-protein kinase Tec, and its interaction with tyrosine-protein kinase Tec is phosphorylation-dependent. This protein is thought to participate in a positive feedback loop by upregulating the activity of tyrosine-protein kinase Tec. Variants of this gene have been associated with autosomal-dominant hypercholesterolemia (ADH), which is characterized by elevated low-density lipoprotein cholesterol levels and in increased risk of coronary vascular disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAP1	NM_012108.4	c.157A>C	p.Thr53Pro	missense_variant	2/9	ENST00000265404.7	NP_036240.1
STAP1	NM_001317769.2	c.157A>C	p.Thr53Pro	missense_variant	2/10		NP_001304698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAP1	ENST00000265404.7	c.157A>C	p.Thr53Pro	missense_variant	2/9	1	NM_012108.4	ENSP00000265404.2
STAP1	ENST00000396225.1	c.157A>C	p.Thr53Pro	missense_variant	2/10	1		ENSP00000379527.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The p.T53P variant (also known as c.157A>C), located in coding exon 2 of the STAP1 gene, results from an A to C substitution at nucleotide position 157. The threonine at codon 53 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.61	.;T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.068	T;T
Polyphen		0.75	P;P
Vest4		0.65
MutPred		0.72		Loss of catalytic residue at F56 (P = 0.1598);Loss of catalytic residue at F56 (P = 0.1598);
MVP		0.84
MPC		0.35
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.74
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-68436838;