10-87709196-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

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:3
• Conservation: PhyloP100: 3.10

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 -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• 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 GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAPSS2	NM_001015880.2	c.28G>A	p.Glu10Lys	missense_variant, splice_region_variant	2/13	ENST00000456849.2
PAPSS2	NM_004670.4	c.28G>A	p.Glu10Lys	missense_variant, splice_region_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAPSS2	ENST00000456849.2	c.28G>A	p.Glu10Lys	missense_variant, splice_region_variant	2/13	1	NM_001015880.2	A1
PAPSS2	ENST00000361175.8	c.28G>A	p.Glu10Lys	missense_variant, splice_region_variant	2/12	1		P4
PAPSS2	ENST00000465996.5	n.50G>A		splice_region_variant, non_coding_transcript_exon_variant	2/3	2
PAPSS2	ENST00000482258.1	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.: 17 Cov.: 32

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.: 28 AF XY: 0.0134 AC XY: 1824 AN XY: 135822

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.: 28 AF XY: 0.0193 AC XY: 13948 AN XY: 721230

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.: 17 Cov.: 32 AF XY: 0.0122 AC XY: 911 AN XY: 74408

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.: 35

Bravo AF: 0.0130

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0275 AC: 106

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0215 AC: 185

ExAC AF: 0.0138 AC: 1679

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.0182

EpiControl AF: 0.0190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 07, 2016

- -

Spondyloepimetaphyseal dysplasia, PAPSS2 type Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 17, 2019

This variant is associated with the following publications: (PMID: 11773860) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.075	T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Uncertain	0.54	T
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	T
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

Other links and lift over

dbSNP: rs17173698; hg19: chr10-89468953; COSMIC: COSV63263743;