Variant 4-56459380-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001079524.2(PAICS):c.1120T>A(p.Cys374Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,434,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PAICS
NM_001079524.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.35

Variant links:

Genes affected

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAICS	NM_001079524.2 linkuse as main transcript	c.1120T>A	p.Cys374Ser	missense_variant	9/9	ENST00000512576.3	NP_001072992.1	P22234-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAICS	ENST00000512576.3 linkuse as main transcript	c.1120T>A	p.Cys374Ser	missense_variant	9/9	1	NM_001079524.2	ENSP00000421096.1		P22234-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000124

AC:

AN:

241954

Hom.:

AF XY:

0.0000153

AC XY:

AN XY:

131052

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1434598

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

710050

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.14e-7

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000248

AC:

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

Oct 05, 2022

The c.1141T>A (p.C381S) alteration is located in exon 10 (coding exon 10) of the PAICS gene. This alteration results from a T to A substitution at nucleotide position 1141, causing the cysteine (C) at amino acid position 381 to be replaced by a serine (S). 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

Uncertain

0.45

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

.;T;T;.;T

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.79

T;.;T;T;T

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.89

D;D;D;D;D

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.5

.;M;.;.;M

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-8.5

D;D;D;D;D

REVEL

Uncertain

0.41

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

0.98, 0.99, 1.0

.;D;D;D;D

Vest4

0.50

MutPred

0.75

.;Gain of disorder (P = 1e-04);Gain of disorder (P = 1e-04);.;Gain of disorder (P = 1e-04);

MVP

0.69

MPC

0.53

ClinPred

0.99

GERP RS

3.8

Varity_R

0.95

gMVP

0.93

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