rs1407030695

Variant names:

• chr4-107614323-G-T
• rs1407030695
• NM_005443.5:c.1801C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005443.5(PAPSS1):​c.1801C>A​(p.Pro601Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,628 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: 6.8e-7 (0 hom.)
• Consequence: PAPSS1 NM_005443.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.37
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005443.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPSS1	NM_005443.5	MANE Select	c.1801C>A	p.Pro601Thr	missense	Exon 12 of 12	NP_005434.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPSS1	ENST00000265174.5	TSL:1 MANE Select	c.1801C>A	p.Pro601Thr	missense	Exon 12 of 12	ENSP00000265174.4	O43252
	PAPSS1	ENST00000873396.1		c.1870C>A	p.Pro624Thr	missense	Exon 13 of 13	ENSP00000543455.1
	PAPSS1	ENST00000970503.1		c.1798C>A	p.Pro600Thr	missense	Exon 12 of 12	ENSP00000640562.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251186 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461628 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727120

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111794

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		9.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.69		Gain of phosphorylation at P601 (P = 0.0083)
MVP		0.87
MPC		1.2
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.98
gMVP		0.86
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs1407030695; hg19: chr4-108535479;