Genetic Variant NM_012108.4:c.139A>C (chr4-67571102-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_012108.4(STAP1):c.139A>C(p.Thr47Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T47A) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

STAP1
NM_012108.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.78

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-67571102-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 189309.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.847

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012108.4. 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
	STAP1	NM_012108.4	MANE Select	c.139A>C	p.Thr47Pro	missense	Exon 2 of 9	NP_036240.1	Q9ULZ2
	STAP1	NM_001317769.2		c.139A>C	p.Thr47Pro	missense	Exon 2 of 10	NP_001304698.1	Q9ULZ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STAP1	ENST00000265404.7	TSL:1 MANE Select	c.139A>C	p.Thr47Pro	missense	Exon 2 of 9	ENSP00000265404.2	Q9ULZ2
STAP1	ENST00000396225.1	TSL:1	c.139A>C	p.Thr47Pro	missense	Exon 2 of 10	ENSP00000379527.1	Q9ULZ2
STAP1	ENST00000894638.1		c.139A>C	p.Thr47Pro	missense	Exon 3 of 10	ENSP00000564697.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

Eigen

Benign

0.054

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.67

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.6

PhyloP100

3.8

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.26

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.011

Polyphen

0.18

Vest4

0.68

MutPred

0.81

Loss of sheet (P = 0.0817)

MVP

0.26

MPC

0.24

ClinPred

0.95

GERP RS

4.4

Varity_R

0.54

gMVP

0.71

Mutation Taster

=47/53

disease causing

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over