rs793888522

Variant names:

• chr4-67571102-A-C
• rs793888522
• NM_012108.4:c.139A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-67571102-A-C
• chr4-67571102-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.78
• Publications: 0 publications found

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

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

Sel.	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.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	0.054
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.26
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.011	D
Polyphen		0.18	B
Vest4		0.68
MutPred		0.81		Loss of sheet (P = 0.0817)
MVP		0.26
MPC		0.24
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.54
gMVP		0.71
Mutation Taster		=47/53	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

dbSNP: rs793888522; hg19: chr4-68436820;