rs121908951

chr10-87709311-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001015880.2(PAPSS2):c.143C>G(p.Thr48Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000215 in 1,395,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: PAPSS2 NM_001015880.2 missense, splice_region
• Scores: Splicing: ADA: 0.8330
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.78

Genes affected

PAPSS2 (HGNC:8604): (3'-phosphoadenosine 5'-phosphosulfate synthase 2) Sulfation is a common modification of endogenous (lipids, proteins, and carbohydrates) and exogenous (xenobiotics and drugs) compounds. In mammals, the sulfate source is 3'-phosphoadenosine 5'-phosphosulfate (PAPS), created from ATP and inorganic sulfate. Two different tissue isoforms encoded by different genes synthesize PAPS. This gene encodes one of the two PAPS synthetases. Defects in this gene cause the Pakistani type of spondyloepimetaphyseal dysplasia. Two alternatively spliced transcript variants that encode different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 10-87709311-C-G is Pathogenic according to our data. Variant chr10-87709311-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 6687.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAPSS2	NM_001015880.2	c.143C>G	p.Thr48Arg	missense_variant, splice_region_variant	2/13	ENST00000456849.2
PAPSS2	NM_004670.4	c.143C>G	p.Thr48Arg	missense_variant, splice_region_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAPSS2	ENST00000456849.2	c.143C>G	p.Thr48Arg	missense_variant, splice_region_variant	2/13	1	NM_001015880.2	A1
PAPSS2	ENST00000361175.8	c.143C>G	p.Thr48Arg	missense_variant, splice_region_variant	2/12	1		P4
PAPSS2	ENST00000465996.5	n.165C>G		splice_region_variant, non_coding_transcript_exon_variant	2/3	2
PAPSS2	ENST00000482258.1	n.186C>G		splice_region_variant, non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1395246 Hom.: 0 Cov.: 23 AF XY: 0.00000430 AC XY: 3 AN XY: 697920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.51e-7

Gnomad4 OTH exome AF: 0.0000344

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spondyloepimetaphyseal dysplasia, PAPSS2 type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 28, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.9	H;H
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.95
MutPred		0.95		Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);
MVP		0.98
MPC		0.84
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.83
dbscSNV1_RF	Benign	0.63
SpliceAI score (max)		0.040		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: rs121908951; hg19: chr10-89469068;