4-56412149-A-T

Variant names:

• chr4-56412149-A-T
• rs9683679
• NM_002703.5:c.129-4433T>A

Variant summary

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

The NM_002703.5(PPAT):​c.129-4433T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 151,940 control chromosomes in the GnomAD database, including 35,347 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 0.68 (35347 hom., cov: 30)
• Consequence: PPAT NM_002703.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.12
• Publications: 10 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002703.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPAT	NM_002703.5	MANE Select	c.129-4433T>A		intron	N/A	NP_002694.3
	PAICS	NM_001392010.1		c.382+1252A>T		intron	N/A	NP_001378939.1
	PAICS	NM_001392011.1		c.382+1252A>T		intron	N/A	NP_001378940.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPAT	ENST00000264220.6	TSL:1 MANE Select	c.129-4433T>A		intron	N/A	ENSP00000264220.2
	PPAT	ENST00000507724.1	TSL:3	n.129-4433T>A		intron	N/A	ENSP00000425119.1
	PPAT	ENST00000510643.5	TSL:5	n.129-4433T>A		intron	N/A	ENSP00000423781.1

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103401 AN: 151822 Hom.: 35320 Cov.: 30

Gnomad AFR AF: 0.662

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.595

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.667

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.681 AC: 103479 AN: 151940 Hom.: 35347 Cov.: 30 AF XY: 0.687 AC XY: 51032 AN XY: 74292

African (AFR) AF: 0.662 AC: 27397 AN: 41392

American (AMR) AF: 0.759 AC: 11581 AN: 15266

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

East Asian (EAS) AF: 0.707 AC: 3646 AN: 5154

South Asian (SAS) AF: 0.727 AC: 3497 AN: 4812

European-Finnish (FIN) AF: 0.752 AC: 7940 AN: 10560

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.665 AC: 45224 AN: 67974

Other (OTH) AF: 0.662 AC: 1399 AN: 2112

Alfa AF: 0.668 Hom.: 4198

Bravo AF: 0.680

Asia WGS AF: 0.707 AC: 2461 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.092
DANN	Benign	0.75
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs9683679; hg19: chr4-57278315;