Variant 4-56407657-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_002703.5(PPAT):c.188C>T(p.Ser63Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000932 in 1,599,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

PPAT
NM_002703.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.59

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2

Missense variant where missense usually causes diseases, PPAT

BP4

Computational evidence support a benign effect (MetaRNN=0.009182155).

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPAT	NM_002703.5 linkuse as main transcript	c.188C>T	p.Ser63Leu	missense_variant	2/11	ENST00000264220.6
PPAT	NR_156493.2 linkuse as main transcript	n.326C>T		non_coding_transcript_exon_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PPAT	ENST00000264220.6 linkuse as main transcript	c.188C>T	p.Ser63Leu	missense_variant	2/11	1	NM_002703.5	P1
PPAT	ENST00000507648.5 linkuse as main transcript	n.290C>T		non_coding_transcript_exon_variant	2/7	5
PPAT	ENST00000510643.5 linkuse as main transcript	c.188C>T	p.Ser63Leu	missense_variant, NMD_transcript_variant	2/6	5
PPAT	ENST00000507724.1 linkuse as main transcript	c.188C>T	p.Ser63Leu	missense_variant, NMD_transcript_variant	2/5	3

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000175

AC:

AN:

251452

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000891

AC:

129

AN:

1447076

Hom.:

Cov.:

AF XY:

0.0000832

AC XY:

AN XY:

720796

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00380

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000137

Gnomad4 OTH exome

AF:

0.000233

GnomAD4 genome

AF:

0.000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000446

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2024

The c.188C>T (p.S63L) alteration is located in exon 2 (coding exon 2) of the PPAT gene. This alteration results from a C to T substitution at nucleotide position 188, causing the serine (S) at amino acid position 63 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.093

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.49

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.016

MetaRNN

Benign

0.0092

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.17

MutationTaster

Benign

1.0

PrimateAI

Benign

0.36

PROVEAN

Benign

1.3

REVEL

Benign

0.065

Sift

Benign

0.63

Sift4G

Benign

0.68

Polyphen

0.0

Vest4

0.10

MVP

0.28

MPC

0.86

ClinPred

0.032

GERP RS

3.4

Varity_R

0.044

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over