Genetic Variant PRPSAP2:p.Met46Lys (chr17-18867299-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_001353096.1(PRPSAP2):c.2T>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000205 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PRPSAP2
NM_001353096.1 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.40

Variant links:

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]

PRPSAP2 links:

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ACMG classification

Classification made for transcript

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 42 codons. Genomic position: 18877717. Lost 0.127 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 link	c.137T>A	p.Met46Lys	missense_variant	Exon 4 of 12	ENST00000268835.7	NP_002758.1	O60256-1A0A024QYY3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPSAP2	ENST00000268835.7 link	c.137T>A	p.Met46Lys	missense_variant	Exon 4 of 12	1	NM_002767.4	ENSP00000268835.2		O60256-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251476

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.137T>A (p.M46K) alteration is located in exon 4 (coding exon 2) of the PRPSAP2 gene. This alteration results from a T to A substitution at nucleotide position 137, causing the methionine (M) at amino acid position 46 to be replaced by a lysine (K). 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

0.24

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Uncertain

0.62

.;D;.;.;.;.;D;D;D;.;.

Eigen

Benign

0.078

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;.;D;D;.;D;D;D;D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.69

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

0.95

.;.;.;.;.;.;L;.;.;.;L

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.8

D;D;D;.;.;D;D;D;.;D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.021

D;D;D;.;.;D;D;D;.;D;D

Sift4G

Uncertain

0.028

D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.076

.;.;.;.;.;.;B;.;.;.;.

Vest4

0.70, 0.71

MutPred

0.72

Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);Gain of disorder (P = 0.0136);

MVP

0.97

MPC

1.4

ClinPred

0.90

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over