17-18865884-A-C

Variant summary

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

The NM_002767.4(PRPSAP2):c.51A>C(p.Lys17Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000323 in 1,549,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PRPSAP2 NM_002767.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24

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=0.33424062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPSAP2	NM_002767.4	c.51A>C	p.Lys17Asn	missense_variant	3/12	ENST00000268835.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPSAP2	ENST00000268835.7	c.51A>C	p.Lys17Asn	missense_variant	3/12	1	NM_002767.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1396914 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 693204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000484

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: 0.00

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74324

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000680

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

Dec 18, 2023

The c.51A>C (p.K17N) alteration is located in exon 3 (coding exon 1) of the PRPSAP2 gene. This alteration results from a A to C substitution at nucleotide position 51, causing the lysine (K) at amino acid position 17 to be replaced by an asparagine (N). 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	0.31
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Benign	0.090
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	0.97	D;.;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.82	N;N;N;.;.;N;N;N;N;.;.;.;N;.;N
REVEL	Uncertain	0.40
Sift	Benign	0.15	T;D;T;.;.;T;T;D;D;.;.;.;D;.;D
Sift4G	Benign	0.34	T;T;T;T;T;T;T;T;T;D;D;T;T;D;T
Polyphen		0.61	.;.;.;.;.;.;.;P;.;.;.;.;.;.;.
Vest4		0.70, 0.64, 0.85, 0.57
MutPred		0.42		Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);Loss of ubiquitination at K17 (P = 0.0161);
MVP		0.92
MPC		1.5
ClinPred		0.74	D
GERP RS		4.7
Varity_R		0.21
gMVP		0.45

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

LitVar

Other links and lift over

dbSNP: rs887474957; hg19: chr17-18769197;