rs17173698

Positions:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001015880.2(PAPSS2):c.28G>A(p.Glu10Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,599,836 control chromosomes in the GnomAD database, including 370 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 17 hom., cov: 32)

Exomes 𝑓: 0.020 ( 353 hom. )

Consequence

PAPSS2
NM_001015880.2 missense, splice_region

Scores

Splicing: ADA: 0.9972

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.10

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 links:

PAPSS2 (HGNC:):

PAPSS2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 10-87709196-G-A is Benign according to our data. Variant chr10-87709196-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 288334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87709196-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0131 (1999/152188) while in subpopulation NFE AF= 0.0211 (1432/67992). AF 95% confidence interval is 0.0202. There are 17 homozygotes in gnomad4. There are 911 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAPSS2	NM_001015880.2 linkuse as main transcript	c.28G>A	p.Glu10Lys	missense_variant, splice_region_variant	2/13	ENST00000456849.2	NP_001015880.1	O95340-2
PAPSS2	NM_004670.4 linkuse as main transcript	c.28G>A	p.Glu10Lys	missense_variant, splice_region_variant	2/12		NP_004661.2	O95340-1Q5TB52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PAPSS2	ENST00000456849.2 linkuse as main transcript	c.28G>A	p.Glu10Lys	missense_variant, splice_region_variant	2/13	1	NM_001015880.2	ENSP00000406157.1	O95340-2
PAPSS2	ENST00000361175.8 linkuse as main transcript	c.28G>A	p.Glu10Lys	missense_variant, splice_region_variant	2/12	1		ENSP00000354436.4	O95340-1
PAPSS2	ENST00000465996.5 linkuse as main transcript	n.50G>A		splice_region_variant, non_coding_transcript_exon_variant	2/3	2
PAPSS2	ENST00000482258.1 linkuse as main transcript	n.71G>A		splice_region_variant, non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2002

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00331

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.0234

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0129

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0211

Gnomad OTH

AF:

0.00863

GnomAD3 exomes

AF:

0.0133

AC:

3343

AN:

251322

Hom.:

AF XY:

0.0134

AC XY:

1824

AN XY:

135822

show subpopulations

Gnomad AFR exome

AF:

0.00344

Gnomad AMR exome

AF:

0.00804

Gnomad ASJ exome

AF:

0.0225

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00193

Gnomad FIN exome

AF:

0.0109

Gnomad NFE exome

AF:

0.0212

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0200

AC:

28898

AN:

1447648

Hom.:

353

Cov.:

AF XY:

0.0193

AC XY:

13948

AN XY:

721230

show subpopulations

Gnomad4 AFR exome

AF:

0.00286

Gnomad4 AMR exome

AF:

0.00890

Gnomad4 ASJ exome

AF:

0.0232

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00192

Gnomad4 FIN exome

AF:

0.0118

Gnomad4 NFE exome

AF:

0.0237

Gnomad4 OTH exome

AF:

0.0160

GnomAD4 genome

AF:

0.0131

AC:

1999

AN:

152188

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

911

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00330

Gnomad4 AMR

AF:

0.0122

Gnomad4 ASJ

AF:

0.0234

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00146

Gnomad4 FIN

AF:

0.0129

Gnomad4 NFE

AF:

0.0211

Gnomad4 OTH

AF:

0.00854

Alfa

AF:

0.0183

Hom.:

Bravo

AF:

0.0130

TwinsUK

AF:

0.0218

AC:

ALSPAC

AF:

0.0275

AC:

106

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0215

AC:

185

ExAC

AF:

0.0138

AC:

1679

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.0182

EpiControl

AF:

0.0190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2019	This variant is associated with the following publications: (PMID: 11773860) -

Spondyloepimetaphyseal dysplasia, PAPSS2 type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.075

T;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.59

T;T

MetaRNN

Benign

0.0032

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

L;L

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.57

N;N

REVEL

Benign

0.086

Sift

Benign

0.25

T;T

Sift4G

Benign

0.43

T;T

Polyphen

0.0

B;B

Vest4

0.15

MPC

0.23

ClinPred

0.019

GERP RS

4.8

Varity_R

0.11

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.86

SpliceAI score (max)

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over