NM_005443.5:c.1855A>C

Variant names:

• chr4-107614269-T-G
• NM_005443.5:c.1855A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005443.5(PAPSS1):​c.1855A>C​(p.Lys619Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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: 0.936
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06052178).

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.1855A>C	p.Lys619Gln	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.1855A>C	p.Lys619Gln	missense	Exon 12 of 12	ENSP00000265174.4	O43252
	PAPSS1	ENST00000873396.1		c.1924A>C	p.Lys642Gln	missense	Exon 13 of 13	ENSP00000543455.1
	PAPSS1	ENST00000970503.1		c.1852A>C	p.Lys618Gln	missense	Exon 12 of 12	ENSP00000640562.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461424 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727000

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111734

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 32

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	Benign	0.065
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.30
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.73	N
PhyloP100		0.94
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.32		Loss of methylation at K619 (P = 0.015)
MVP		0.32
MPC		0.36
ClinPred		0.60	D
GERP RS		6.2
Varity_R		0.28
gMVP		0.56
Mutation Taster		=68/32	polymorphism

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

hg19: chr4-108535425;