17-18911182-G-C

Position:

• chr17-18911182-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002767.4(PRPSAP2):​c.664G>C​(p.Val222Leu) 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 benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRPSAP2 NM_002767.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.66

Genes affected

PRPSAP2 (HGNC:9467): (phosphoribosyl pyrophosphate synthetase associated protein 2) This gene encodes a protein that associates with the enzyme phosphoribosylpyrophosphate synthetase (PRS). PRS catalyzes the formation of phosphoribosylpyrophosphate which is a substrate for synthesis of purine and pyrimidine nucleotides, histidine, tryptophan and NAD. PRS exists as a complex with two catalytic subunits and two associated subunits. This gene encodes a non-catalytic associated subunit of PRS. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33729032).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPSAP2	NM_002767.4	c.664G>C	p.Val222Leu	missense_variant	9/12	ENST00000268835.7	NP_002758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPSAP2	ENST00000268835.7	c.664G>C	p.Val222Leu	missense_variant	9/12	1	NM_002767.4	ENSP00000268835.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Nov 21, 2024

The c.664G>C (p.V222L) alteration is located in exon 9 (coding exon 7) of the PRPSAP2 gene. This alteration results from a G to C substitution at nucleotide position 664, causing the valine (V) at amino acid position 222 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.37	T;.;.;.;T;T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.035
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;.;D;D;D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.94	.;.;.;.;L;.;.;L
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.81	N;.;N;N;N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.47	T;.;T;T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T;T;T;T
Polyphen		0.0040	.;.;.;.;B;.;.;.
Vest4		0.47, 0.52, 0.46, 0.46, 0.60
MutPred		0.34		Loss of stability (P = 0.1747);.;.;.;Loss of stability (P = 0.1747);Loss of stability (P = 0.1747);Loss of stability (P = 0.1747);Loss of stability (P = 0.1747);
MVP		0.69
MPC		0.91
ClinPred		0.78	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.63

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: chr17-18814495;