rs121908952

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001015880.2(PAPSS2):c.1000C>T(p.Arg334*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,032 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PAPSS2
NM_001015880.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.207

Publications

9 publications found

Variant links:

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]

PAPSS2 Gene-Disease associations (from GenCC):

spondyloepimetaphyseal dysplasia, PAPSS2 type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
autosomal recessive brachyolmia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PAPSS2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-87727403-C-T is Pathogenic according to our data. Variant chr10-87727403-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPSS2	NM_001015880.2 link	c.1000C>T	p.Arg334*	stop_gained	Exon 9 of 13	ENST00000456849.2	NP_001015880.1
PAPSS2	NM_004670.4 link	c.985C>T	p.Arg329*	stop_gained	Exon 8 of 12		NP_004661.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPSS2	ENST00000456849.2 link	c.1000C>T	p.Arg334*	stop_gained	Exon 9 of 13	1	NM_001015880.2	ENSP00000406157.1
PAPSS2	ENST00000361175.8 link	c.985C>T	p.Arg329*	stop_gained	Exon 8 of 12	1		ENSP00000354436.4

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000359

AC:

AN:

250816

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39678

South Asian (SAS)

AF:

0.000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000415

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00000473

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spondyloepimetaphyseal dysplasia, PAPSS2 type

Pathogenic:5

Jan 03, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000036, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000006688, PMID:19474428). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

May 28, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 03, 2019

Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg334*) in the PAPSS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAPSS2 are known to be pathogenic (PMID: 22791835, 23633440). This variant is present in population databases (rs121908952, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with brachyolmia (PMID: 23633440, 31313512). This variant is also known as p.R329X . ClinVar contains an entry for this variant (Variation ID: 6688). For these reasons, this variant has been classified as Pathogenic. -

Sep 01, 2017

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 7-year-old male with IUGR, failure to thrive, microcephaly, chondrodystrophy, severe kyphoscoliosis, asymmetric chest with rib flaring, mild knee contractures, asymmetric face with maxillary and orbital hypoplasia, dysmorphism, hypotonia, PDA -

Autosomal recessive brachyolmia

Pathogenic:1

Apr 10, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1000C>T;p.(Arg334*) variant creates a premature translational stop signal in the PAPSS2 gene. It is expected to result in an absent or disrupted protein product -PVS1.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 19474428)PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 6688; PMID: 19474428; DOI:10.1186/s13073-019-0651-9) - PS4. The variant is present at low allele frequencies population databases (rs121908952 – gnomAD 0.0001972%; ABraOM no frequency - https://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg334*) was detected in trans with a pathogenic variant (PMID: 19474428; DOI:10.1186/s13073-019-0651-9) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -

not provided

Pathogenic:1

Nov 06, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.031

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.083

PhyloP100

0.21

Vest4

0.82

GERP RS

1.3

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over