4-56448559-T-C

Position:

• chr4-56448559-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001079524.2(PAICS):​c.535T>C​(p.Ser179Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAICS NM_001079524.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.94

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
• PP5: Variant 4-56448559-T-C is Pathogenic according to our data. Variant chr4-56448559-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3242227.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAICS	NM_001079524.2	c.535T>C	p.Ser179Pro	missense_variant	4/9	ENST00000512576.3	NP_001072992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAICS	ENST00000512576.3	c.535T>C	p.Ser179Pro	missense_variant	4/9	1	NM_001079524.2	ENSP00000421096.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Phosphoribosylaminoimidazole carboxylase deficiency Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Biochemical Genetics Laboratory, National Taiwan University

Nov 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T;T;.;T
Eigen	Benign	-0.022
Eigen_PC	Benign	0.056
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;.;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	.;M;.;.;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.016	D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D
Polyphen		0.51, 0.59	.;P;P;P;P
Vest4		0.68
MutPred		0.63		.;Gain of catalytic residue at S179 (P = 0.0111);Gain of catalytic residue at S179 (P = 0.0111);.;Gain of catalytic residue at S179 (P = 0.0111);
MVP		0.71
MPC		0.39
ClinPred		0.88	D
GERP RS		3.0
Varity_R		0.91
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-57314725;