10-87727289-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001015880.2(PAPSS2):c.886G>A(p.Val296Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,612,812 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 5 hom., cov: 32)

Exomes 𝑓: 0.012 ( 136 hom. )

Consequence

PAPSS2
NM_001015880.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.13

Publications

12 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008572251).

BP6

Variant 10-87727289-G-A is Benign according to our data. Variant chr10-87727289-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 500278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00845 (1286/152278) while in subpopulation NFE AF = 0.0142 (966/68018). AF 95% confidence interval is 0.0135. There are 5 homozygotes in GnomAd4. There are 589 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPSS2	NM_001015880.2 link	c.886G>A	p.Val296Met	missense_variant	Exon 9 of 13	ENST00000456849.2	NP_001015880.1	O95340-2
PAPSS2	NM_004670.4 link	c.871G>A	p.Val291Met	missense_variant	Exon 8 of 12		NP_004661.2	O95340-1Q5TB52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPSS2	ENST00000456849.2 link	c.886G>A	p.Val296Met	missense_variant	Exon 9 of 13	1	NM_001015880.2	ENSP00000406157.1		O95340-2
PAPSS2	ENST00000361175.8 link	c.871G>A	p.Val291Met	missense_variant	Exon 8 of 12	1		ENSP00000354436.4		O95340-1

Frequencies

GnomAD3 genomes

AF:

0.00845

AC:

1286

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00261

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00891

Gnomad ASJ

AF:

0.00923

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000943

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0142

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00815

AC:

2046

AN:

250964

AF XY:

0.00835

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00665

Gnomad ASJ exome

AF:

0.00766

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.0139

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.0123

AC:

18002

AN:

1460534

Hom.:

136

Cov.:

AF XY:

0.0121

AC XY:

8797

AN XY:

726628

show subpopulations

African (AFR)

AF:

0.00266

AC:

AN:

33454

American (AMR)

AF:

0.00671

AC:

300

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00739

AC:

193

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00160

AC:

138

AN:

86204

European-Finnish (FIN)

AF:

0.00133

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.0210

AC:

104

AN:

4958

European-Non Finnish (NFE)

AF:

0.0149

AC:

16543

AN:

1111672

Other (OTH)

AF:

0.00936

AC:

564

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

881

1763

2644

3526

4407

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

616

1232

1848

2464

3080

<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:

0.00845

AC:

1286

AN:

152278

Hom.:

Cov.:

AF XY:

0.00791

AC XY:

589

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00260

AC:

108

AN:

41570

American (AMR)

AF:

0.00889

AC:

136

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00923

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000943

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0142

AC:

966

AN:

68018

Other (OTH)

AF:

0.0104

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

134

202

269

336

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0129

Hom.:

Bravo

AF:

0.00912

TwinsUK

AF:

0.0208

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0130

AC:

112

ExAC

AF:

0.00789

AC:

958

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PAPSS2: BP4, BS1, BS2 -

not specified

Benign:1

Feb 21, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spondyloepimetaphyseal dysplasia, PAPSS2 type

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.49

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

T;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

D;D

MetaRNN

Benign

0.0086

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;.

PhyloP100

3.1

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.056

Sift

Benign

0.071

T;T

Sift4G

Benign

0.073

T;T

Polyphen

0.46

P;P

Vest4

0.52

MVP

0.55

MPC

0.50

ClinPred

0.0083

GERP RS

5.7

Varity_R

0.064

gMVP

0.54

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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