rs45467596

Positions:

• chr10-87727289-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (5 hom., cov: 32)
  • Exomes 𝑓: 0.012 (136 hom.)
• Consequence: PAPSS2 NM_001015880.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.13

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]

ACMG classification

Verdict is Benign. Variant got -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]. Clinvar id is 500278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87727289-G-A is described in Lovd as [Likely_benign]. Variant chr10-87727289-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAPSS2	NM_001015880.2	c.886G>A	p.Val296Met	missense_variant	9/13	ENST00000456849.2
PAPSS2	NM_004670.4	c.871G>A	p.Val291Met	missense_variant	8/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAPSS2	ENST00000456849.2	c.886G>A	p.Val296Met	missense_variant	9/13	1	NM_001015880.2	A1
PAPSS2	ENST00000361175.8	c.871G>A	p.Val291Met	missense_variant	8/12	1		P4

Frequencies

GnomAD3 genomes AF: 0.00845 AC: 1286 AN: 152160 Hom.: 5 Cov.: 32

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

GnomAD3 exomes AF: 0.00815 AC: 2046 AN: 250964 Hom.: 14 AF XY: 0.00835 AC XY: 1132 AN XY: 135644

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 SAS exome AF: 0.00118

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.: 32 AF XY: 0.0121 AC XY: 8797 AN XY: 726628

Gnomad4 AFR exome AF: 0.00266

Gnomad4 AMR exome AF: 0.00671

Gnomad4 ASJ exome AF: 0.00739

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.00133

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.00936

GnomAD4 genome AF: 0.00845 AC: 1286 AN: 152278 Hom.: 5 Cov.: 32 AF XY: 0.00791 AC XY: 589 AN XY: 74464

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.00923

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000943

Gnomad4 NFE AF: 0.0142

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0133 Hom.: 29

Bravo AF: 0.00912

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0130 AC: 112

ExAC AF: 0.00789 AC: 958

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondyloepimetaphyseal dysplasia, PAPSS2 type Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 21, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

PAPSS2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D
MetaRNN	Benign	0.0086	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Benign	0.46	T
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	T
GERP RS		5.7
Varity_R		0.064
gMVP		0.54

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

LitVar

Other links and lift over

dbSNP: rs45467596; hg19: chr10-89487046;