rs2139512

Variant names:

• chr4-56410453-G-C
• rs2139512
• NM_002703.5:c.129-2737C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002703.5(PPAT):​c.129-2737C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.674 in 914,172 control chromosomes in the GnomAD database, including 207,739 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.69 (35988 hom., cov: 30)
  • Exomes 𝑓: 0.67 (171751 hom.)
• Consequence: PPAT NM_002703.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.90
• Publications: 7 publications found

Genes affected

PPAT (HGNC:9238): (phosphoribosyl pyrophosphate amidotransferase) The protein encoded by this gene is a member of the purine/pyrimidine phosphoribosyltransferase family. It is a regulatory allosteric enzyme that catalyzes the first step of de novo purine nucleotide biosythetic pathway. This gene and PAICS/AIRC gene, a bifunctional enzyme catalyzing steps six and seven of this pathway, are located in close proximity on chromosome 4, and divergently transcribed from an intergenic region. [provided by RefSeq, Mar 2011]

PAICS (HGNC:8587): (phosphoribosylaminoimidazole carboxylase and phosphoribosylaminoimidazolesuccinocarboxamide synthase) This gene encodes a bifunctional enzyme containing phosphoribosylaminoimidazole carboxylase activity in its N-terminal region and phosphoribosylaminoimidazole succinocarboxamide synthetase in its C-terminal region. It catalyzes steps 6 and 7 of purine biosynthesis. The gene is closely linked and divergently transcribed with a locus that encodes an enzyme in the same pathway, and transcription of the two genes is coordinately regulated. The human genome contains several pseudogenes of this gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PAICS Gene-Disease associations (from GenCC):

• PAICS deficiency

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000290817 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPAT	NM_002703.5	c.129-2737C>G		intron_variant	Intron 1 of 10	ENST00000264220.6	NP_002694.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPAT	ENST00000264220.6	c.129-2737C>G		intron_variant	Intron 1 of 10	1	NM_002703.5	ENSP00000264220.2

Frequencies

GnomAD3 genomes AF: 0.687 AC: 104316 AN: 151792 Hom.: 35952 Cov.: 30

Gnomad AFR AF: 0.679

Gnomad AMI AF: 0.606

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.763

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.674

GnomAD4 exome AF: 0.671 AC: 511471 AN: 762264 Hom.: 171751 AF XY: 0.671 AC XY: 237331 AN XY: 353842

African (AFR) AF: 0.687 AC: 9865 AN: 14350

American (AMR) AF: 0.772 AC: 713 AN: 924

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2725 AN: 4686

East Asian (EAS) AF: 0.728 AC: 2401 AN: 3298

South Asian (SAS) AF: 0.769 AC: 11611 AN: 15092

European-Finnish (FIN) AF: 0.763 AC: 200 AN: 262

Middle Eastern (MID) AF: 0.628 AC: 965 AN: 1536

European-Non Finnish (NFE) AF: 0.668 AC: 465944 AN: 697170

Other (OTH) AF: 0.683 AC: 17047 AN: 24946

GnomAD4 genome AF: 0.687 AC: 104412 AN: 151908 Hom.: 35988 Cov.: 30 AF XY: 0.694 AC XY: 51525 AN XY: 74256

African (AFR) AF: 0.679 AC: 28128 AN: 41406

American (AMR) AF: 0.760 AC: 11601 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 2064 AN: 3470

East Asian (EAS) AF: 0.711 AC: 3654 AN: 5142

South Asian (SAS) AF: 0.764 AC: 3673 AN: 4810

European-Finnish (FIN) AF: 0.752 AC: 7935 AN: 10548

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.665 AC: 45200 AN: 67960

Other (OTH) AF: 0.675 AC: 1425 AN: 2112

Alfa AF: 0.671 Hom.: 4236

Bravo AF: 0.685

Asia WGS AF: 0.738 AC: 2569 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.70
PhyloP100		1.9
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2139512; hg19: chr4-57276619;