4-67558915-C-T

Position:

chr4-67558915-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000265404.7(STAP1):c.106C>T(p.Arg36Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R36Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

STAP1
ENST00000265404.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.288

Variant links:

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]

STAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STAP1	NM_012108.4 linkuse as main transcript	c.106C>T	p.Arg36Trp	missense_variant	1/9	ENST00000265404.7	NP_036240.1
STAP1	NM_001317769.2 linkuse as main transcript	c.106C>T	p.Arg36Trp	missense_variant	1/10		NP_001304698.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STAP1	ENST00000265404.7 linkuse as main transcript	c.106C>T	p.Arg36Trp	missense_variant	1/9	1	NM_012108.4	ENSP00000265404	P1
STAP1	ENST00000396225.1 linkuse as main transcript	c.106C>T	p.Arg36Trp	missense_variant	1/10	1		ENSP00000379527	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250120

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1459992

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726300

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2022

The p.R36W variant (also known as c.106C>T), located in coding exon 1 of the STAP1 gene, results from a C to T substitution at nucleotide position 106. The arginine at codon 36 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.095

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;T

Eigen

Benign

-0.050

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.88

.;D

M_CAP

Benign

0.076

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

0.88

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.28

Sift

Uncertain

0.023

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.63

MutPred

0.55

Loss of solvent accessibility (P = 0.0468);Loss of solvent accessibility (P = 0.0468);

MVP

0.51

MPC

0.42

ClinPred

0.91

GERP RS

0.039

Varity_R

0.084

gMVP

0.44

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