4-56441804-A-G

Position:

• chr4-56441804-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP3 PP5 BP4

The NM_001079524.2(PAICS):​c.158A>G​(p.Lys53Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,601,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (0 hom.)
• Consequence: PAICS NM_001079524.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, M_CAP, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 4-56441804-A-G is Pathogenic according to our data. Variant chr4-56441804-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1686821.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.095124185). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAICS	NM_001079524.2	c.158A>G	p.Lys53Arg	missense_variant	2/9	ENST00000512576.3	NP_001072992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAICS	ENST00000512576.3	c.158A>G	p.Lys53Arg	missense_variant	2/9	1	NM_001079524.2	ENSP00000421096.1

Frequencies

GnomAD3 genomes AF: 0.000716 AC: 109 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000793 AC: 180 AN: 226950 Hom.: 0 AF XY: 0.000811 AC XY: 99 AN XY: 122130

Gnomad AFR exome AF: 0.000286

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000764

Gnomad FIN exome AF: 0.000242

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.000355

GnomAD4 exome AF: 0.00116 AC: 1675 AN: 1448934 Hom.: 0 Cov.: 30 AF XY: 0.00111 AC XY: 799 AN XY: 719156

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000704

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000788

Gnomad4 FIN exome AF: 0.000246

Gnomad4 NFE exome AF: 0.00135

Gnomad4 OTH exome AF: 0.00112

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000846 AC XY: 63 AN XY: 74494

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00105 Hom.: 0

Bravo AF: 0.000733

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000543 AC: 2

ESP6500EA AF: 0.000979 AC: 8

ExAC AF: 0.000845 AC: 102

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Phosphoribosylaminoimidazole carboxylase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 28, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T;.;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	.;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.095	T;T;T;T
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.4	M;.;M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D
Polyphen		0.93	P;P;D;P
Vest4		0.93
MVP		0.75
MPC		0.44
ClinPred		0.13	T
GERP RS		5.5
Varity_R		0.89
gMVP		0.89

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

Other links and lift over

dbSNP: rs192831239; hg19: chr4-57307970; COSMIC: COSV51710271;