17-18877717-A-G

Variant names:

• chr17-18877717-A-G
• rs2038407217
• ENST00000610773.4:c.1A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001243941.1(PRPSAP2):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PRPSAP2 NM_001243941.1 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 6 codons. Genomic position: 18877732. Lost 0.019 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPSAP2	NM_002767.4	c.259A>G	p.Met87Val	missense_variant	Exon 6 of 12	ENST00000268835.7	NP_002758.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPSAP2	ENST00000268835.7	c.259A>G	p.Met87Val	missense_variant	Exon 6 of 12	1	NM_002767.4	ENSP00000268835.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457252 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724940

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.259A>G (p.M87V) alteration is located in exon 6 (coding exon 4) of the PRPSAP2 gene. This alteration results from a A to G substitution at nucleotide position 259, causing the methionine (M) at amino acid position 87 to be replaced by a valine (V). 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	0.30
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	.;D;.;.;.;.;.;.;.;D;D;D;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;.;.;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;.;.;.;M;.;.;.;M
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.7	D;D;.;D;.;.;D;D;D;D;D;.;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0040	D;D;.;D;.;.;D;D;D;D;D;.;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.93	.;.;.;.;.;.;.;.;.;P;.;.;.;.
Vest4		0.88, 0.82, 0.89, 0.89, 0.87
MutPred		0.67		Gain of catalytic residue at M87 (P = 0.0327);Gain of catalytic residue at M87 (P = 0.0327);.;Gain of catalytic residue at M87 (P = 0.0327);Gain of catalytic residue at M87 (P = 0.0327);Gain of catalytic residue at M87 (P = 0.0327);.;.;Gain of catalytic residue at M87 (P = 0.0327);Gain of catalytic residue at M87 (P = 0.0327);Gain of catalytic residue at M87 (P = 0.0327);Gain of catalytic residue at M87 (P = 0.0327);Gain of catalytic residue at M87 (P = 0.0327);Gain of catalytic residue at M87 (P = 0.0327);
MVP		0.96
MPC		1.8
ClinPred		0.98	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs2038407217; hg19: chr17-18781030;