17-76311564-C-T

Variant names:

• chr17-76311564-C-T
• rs775714352
• NM_002766.3:c.1136G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002766.3(PRPSAP1):​c.1136G>A​(p.Arg379Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,520 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: PRPSAP1 NM_002766.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

Genes affected

PRPSAP1 (HGNC:9466): (phosphoribosyl pyrophosphate synthetase associated protein 1) Enables identical protein binding activity. Predicted to be involved in 5-phosphoribose 1-diphosphate biosynthetic process and purine nucleotide biosynthetic process. Predicted to be part of ribose phosphate diphosphokinase complex. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRPSAP1	NM_002766.3	c.1136G>A	p.Arg379Gln	missense_variant	Exon 10 of 10	ENST00000446526.8	NP_002757.2
PRPSAP1	NM_001330503.2	c.827G>A	p.Arg276Gln	missense_variant	Exon 9 of 9		NP_001317432.1
PRPSAP1	NM_001366236.2	c.827G>A	p.Arg276Gln	missense_variant	Exon 10 of 10		NP_001353165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRPSAP1	ENST00000446526.8	c.1136G>A	p.Arg379Gln	missense_variant	Exon 10 of 10	1	NM_002766.3	ENSP00000414624.2
PRPSAP1	ENST00000324684.8	c.827G>A	p.Arg276Gln	missense_variant	Exon 10 of 10	2		ENSP00000314973.4
PRPSAP1	ENST00000588364.1	n.826G>A		non_coding_transcript_exon_variant	Exon 3 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 250928 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135616

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461520 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727042

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1136G>A (p.R379Q) alteration is located in exon 10 (coding exon 10) of the PRPSAP1 gene. This alteration results from a G to A substitution at nucleotide position 1136, causing the arginine (R) at amino acid position 379 to be replaced by a glutamine (Q). 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
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Uncertain	0.18	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Uncertain	0.55
Sift	Benign	0.064	T;T
Sift4G	Benign	0.092	T;T
Polyphen		1.0	D;.
Vest4		0.67
MVP		0.81
MPC		0.79
ClinPred		0.79	D
GERP RS		5.6
gMVP		0.62

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: rs775714352; hg19: chr17-74307645; COSMIC: COSV53152917; COSMIC: COSV53152917;