17-76330062-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002766.3(PRPSAP1):c.616T>C(p.Ser206Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PRPSAP1 NM_002766.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPSAP1	NM_002766.3	c.616T>C	p.Ser206Pro	missense_variant	6/10	ENST00000446526.8
PRPSAP1	NM_001330503.2	c.307T>C	p.Ser103Pro	missense_variant	5/9
PRPSAP1	NM_001366236.2	c.307T>C	p.Ser103Pro	missense_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPSAP1	ENST00000446526.8	c.616T>C	p.Ser206Pro	missense_variant	6/10	1	NM_002766.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461470 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727064

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

May 24, 2023

The c.616T>C (p.S206P) alteration is located in exon 6 (coding exon 6) of the PRPSAP1 gene. This alteration results from a T to C substitution at nucleotide position 616, causing the serine (S) at amino acid position 206 to be replaced by a proline (P). 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	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	30
Dann	Uncertain	1.0
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Uncertain	-0.093	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;.
Polyphen		0.97	D;.;.;.
Vest4		0.82
MVP		0.71
MPC		1.1
ClinPred		0.97	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.89

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: rs2071304441; hg19: chr17-74326143;