chr10-87709227-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001015880.2(PAPSS2):c.59A>G(p.Tyr20Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,038 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Y20Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PAPSS2
NM_001015880.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.92

Publications

0 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: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPSS2	NM_001015880.2 link	c.59A>G	p.Tyr20Cys	missense_variant	Exon 2 of 13	ENST00000456849.2	NP_001015880.1	O95340-2
PAPSS2	NM_004670.4 link	c.59A>G	p.Tyr20Cys	missense_variant	Exon 2 of 12		NP_004661.2	O95340-1Q5TB52

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAPSS2	ENST00000456849.2 link	c.59A>G	p.Tyr20Cys	missense_variant	Exon 2 of 13	1	NM_001015880.2	ENSP00000406157.1	O95340-2
PAPSS2	ENST00000361175.8 link	c.59A>G	p.Tyr20Cys	missense_variant	Exon 2 of 12	1		ENSP00000354436.4	O95340-1
PAPSS2	ENST00000465996.5 link	n.81A>G		non_coding_transcript_exon_variant	Exon 2 of 3	2
PAPSS2	ENST00000482258.1 link	n.102A>G		non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251390

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461038

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726880

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111358

Other (OTH)

AF:

0.0000166

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 17, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.59A>G (p.Y20C) alteration is located in exon 2 (coding exon 2) of the PAPSS2 gene. This alteration results from a A to G substitution at nucleotide position 59, causing the tyrosine (Y) at amino acid position 20 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Benign

0.034

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.4

M;M

PhyloP100

8.9

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.35

Sift

Benign

0.081

T;T

Sift4G

Uncertain

0.031

D;D

Polyphen

0.94

P;D

Vest4

0.83

MutPred

0.61

Loss of phosphorylation at Y20 (P = 0.0298);Loss of phosphorylation at Y20 (P = 0.0298);

MVP

0.60

MPC

0.87

ClinPred

0.94

GERP RS

5.5

Varity_R

0.23

gMVP

0.80

Mutation Taster

=15/85

disease causing

(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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chr10-87709227-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over