NM_002766.3:c.991G>A

Variant names:

• chr17-76312878-C-T
• rs776866780
• NM_002766.3:c.991G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002766.3(PRPSAP1):​c.991G>A​(p.Val331Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000788 in 1,612,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V331A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: PRPSAP1 NM_002766.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.41
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01341337).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002766.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPSAP1	NM_002766.3	MANE Select	c.991G>A	p.Val331Ile	missense	Exon 9 of 10	NP_002757.2	Q14558-2
	PRPSAP1	NM_001330503.2		c.682G>A	p.Val228Ile	missense	Exon 8 of 9	NP_001317432.1	B4DP31
	PRPSAP1	NM_001366236.2		c.682G>A	p.Val228Ile	missense	Exon 9 of 10	NP_001353165.1	B4DP31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPSAP1	ENST00000446526.8	TSL:1 MANE Select	c.991G>A	p.Val331Ile	missense	Exon 9 of 10	ENSP00000414624.2	Q14558-2
	PRPSAP1	ENST00000908407.1		c.1111G>A	p.Val371Ile	missense	Exon 10 of 11	ENSP00000578466.1
	PRPSAP1	ENST00000922958.1		c.1039G>A	p.Val347Ile	missense	Exon 9 of 10	ENSP00000593017.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000561 AC: 14 AN: 249728 AF XY: 0.0000592

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000767 AC: 112 AN: 1460380 Hom.: 0 Cov.: 30 AF XY: 0.0000798 AC XY: 58 AN XY: 726594

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39662

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.0000873 AC: 97 AN: 1111552

Other (OTH) AF: 0.0000995 AC: 6 AN: 60330

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74324

African (AFR) AF: 0.0000241 AC: 1 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000166

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	7.2
DANN	Benign	0.23
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.93	T
PhyloP100		3.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.74	N
REVEL	Benign	0.14
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.30
MVP		0.067
MPC		0.31
ClinPred		0.079	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
gMVP		0.26
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs776866780; hg19: chr17-74308959;