NM_002767.4:c.220A>C

Variant names:

• chr17-18872630-A-C
• rs2037975216
• NM_002767.4:c.220A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002767.4(PRPSAP2):​c.220A>C​(p.Ile74Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,216 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: 6.9e-7 (0 hom.)
• Consequence: PRPSAP2 NM_002767.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002767.4. 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
	PRPSAP2	NM_002767.4	MANE Select	c.220A>C	p.Ile74Leu	missense	Exon 5 of 12	NP_002758.1	O60256-1
	PRPSAP2	NM_001353098.2		c.382A>C	p.Ile128Leu	missense	Exon 5 of 12	NP_001340027.1
	PRPSAP2	NM_001353101.2		c.220A>C	p.Ile74Leu	missense	Exon 4 of 11	NP_001340030.1	O60256-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPSAP2	ENST00000268835.7	TSL:1 MANE Select	c.220A>C	p.Ile74Leu	missense	Exon 5 of 12	ENSP00000268835.2	O60256-1
	PRPSAP2	ENST00000542013.5	TSL:1	c.220A>C	p.Ile74Leu	missense	Exon 4 of 10	ENSP00000439129.1	O60256-3
	PRPSAP2	ENST00000610773.4	TSL:1	c.-39A>C		5_prime_UTR	Exon 4 of 11	ENSP00000481322.1	O60256-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446216 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720298

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33098

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00 AC: 0 AN: 85804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097968

Other (OTH) AF: 0.0000167 AC: 1 AN: 59930

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.20
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.22	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Uncertain	0.56	D
PhyloP100		5.8
Sift4G	Pathogenic	0.0	D
MVP		0.69
ClinPred		0.85	D
GERP RS		5.4
Varity_R		0.57

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: rs2037975216; hg19: chr17-18775943;