NM_001015880.2:c.1403C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001015880.2(PAPSS2):c.1403C>T(p.Ala468Val) variant causes a missense change. The variant allele was found at a frequency of 0.00066 in 1,614,084 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A468T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 4 hom. )

Consequence

PAPSS2
NM_001015880.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: 4.57

Publications

6 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013674557).

BP6

Variant 10-87743553-C-T is Benign according to our data. Variant chr10-87743553-C-T is described in ClinVar as [Benign]. Clinvar id is 537719.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00215 (328/152246) while in subpopulation AFR AF = 0.00671 (279/41560). AF 95% confidence interval is 0.00607. There are 1 homozygotes in GnomAd4. There are 143 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPSS2	NM_001015880.2 link	c.1403C>T	p.Ala468Val	missense_variant	Exon 11 of 13	ENST00000456849.2	NP_001015880.1	O95340-2
PAPSS2	NM_004670.4 link	c.1388C>T	p.Ala463Val	missense_variant	Exon 10 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.1403C>T	p.Ala468Val	missense_variant	Exon 11 of 13	1	NM_001015880.2	ENSP00000406157.1		O95340-2
PAPSS2	ENST00000361175.8 link	c.1388C>T	p.Ala463Val	missense_variant	Exon 10 of 12	1		ENSP00000354436.4		O95340-1

Frequencies

GnomAD3 genomes

AF:

0.00216

AC:

328

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00673

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00336

GnomAD2 exomes

AF:

0.00100

AC:

251

AN:

250714

AF XY:

0.000893

show subpopulations

Gnomad AFR exome

AF:

0.00874

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00240

Gnomad FIN exome

AF:

0.000508

Gnomad NFE exome

AF:

0.000345

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000504

AC:

737

AN:

1461838

Hom.:

Cov.:

AF XY:

0.000517

AC XY:

376

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00747

AC:

250

AN:

33478

American (AMR)

AF:

0.000291

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00713

AC:

283

AN:

39686

South Asian (SAS)

AF:

0.000139

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000318

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000103

AC:

115

AN:

1111978

Other (OTH)

AF:

0.000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

142

190

237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00215

AC:

328

AN:

152246

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

143

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00671

AC:

279

AN:

41560

American (AMR)

AF:

0.000850

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00271

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68006

Other (OTH)

AF:

0.00332

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00109

Hom.:

Bravo

AF:

0.00232

ESP6500AA

AF:

0.00999

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00127

AC:

154

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Spondyloepimetaphyseal dysplasia, PAPSS2 type

Benign:1

Jan 27, 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

0.13

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.088

T;.

Eigen

Benign

-0.099

Eigen_PC

Benign

-0.035

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.0051

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.

PhyloP100

4.6

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.15

Sift

Benign

0.032

D;D

Sift4G

Benign

0.069

T;T

Polyphen

0.030

B;B

Vest4

0.63

MVP

0.36

MPC

0.23

ClinPred

0.021

GERP RS

5.3

Varity_R

0.11

gMVP

0.64

Mutation Taster

=72/28

polymorphism

(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