4-107631779-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005443.5(PAPSS1):c.1588C>A(p.Pro530Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,826 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: 0.0000021 (0 hom.)
• Consequence: PAPSS1 NM_005443.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.42

Genes affected

PAPSS1 (HGNC:8603): (3'-phosphoadenosine 5'-phosphosulfate synthase 1) Three-prime-phosphoadenosine 5-prime-phosphosulfate (PAPS) is the sulfate donor cosubstrate for all sulfotransferase (SULT) enzymes (Xu et al., 2000 [PubMed 10679223]). SULTs catalyze the sulfate conjugation of many endogenous and exogenous compounds, including drugs and other xenobiotics. In humans, PAPS is synthesized from adenosine 5-prime triphosphate (ATP) and inorganic sulfate by 2 isoforms, PAPSS1 and PAPSS2 (MIM 603005).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAPSS1	NM_005443.5	c.1588C>A	p.Pro530Thr	missense_variant	11/12	ENST00000265174.5
PAPSS1	XM_011532400.3	c.1525C>A	p.Pro509Thr	missense_variant	11/12
PAPSS1	XM_011532401.2	c.1525C>A	p.Pro509Thr	missense_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAPSS1	ENST00000265174.5	c.1588C>A	p.Pro530Thr	missense_variant	11/12	1	NM_005443.5	P1
PAPSS1	ENST00000514815.1	n.26C>A		non_coding_transcript_exon_variant	1/2	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461826 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.1588C>A (p.P530T) alteration is located in exon 11 (coding exon 11) of the PAPSS1 gene. This alteration results from a C to A substitution at nucleotide position 1588, causing the proline (P) at amino acid position 530 to be replaced by a threonine (T). 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	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-7.1	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.56		Loss of disorder (P = 0.1697);
MVP		0.83
MPC		1.2
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.88
gMVP		0.81

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: rs1191132157; hg19: chr4-108552935; COSMIC: COSV99491750;