Genetic Variant PPAT:c.129-4433T>A (chr4-56412149-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.12

Publications

10 publications found

Variant links:

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]

PPAT links:

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

PAICS links:

ENSG00000290817 (HGNC:):

ENSG00000290817 links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPAT	NM_002703.5 link	c.129-4433T>A		intron_variant	Intron 1 of 10	ENST00000264220.6	NP_002694.3	Q06203A8K4H7Q59G63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPAT	ENST00000264220.6 link	c.129-4433T>A		intron_variant	Intron 1 of 10	1	NM_002703.5	ENSP00000264220.2		Q06203

Frequencies

GnomAD3 genomes

AF:

0.681

AC:

103401

AN:

151822

Hom.:

35320

Cov.:

show subpopulations

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.:

AF XY:

0.687

AC XY:

51032

AN XY:

74292

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1651

3302

4953

6604

8255

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

816

1632

2448

3264

4080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.092

(source)

DANN

Benign

0.75

PhyloP100

-2.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over