rs17124941

chr10-87713205-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001015880.2(PAPSS2):c.276T>C(p.Ser92=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,609,440 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (8 hom., cov: 28)
  • Exomes 𝑓: 0.0033 (103 hom.)
• Consequence: PAPSS2 NM_001015880.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.249

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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-87713205-T-C is Benign according to our data. Variant chr10-87713205-T-C is described in ClinVar as [Benign]. Clinvar id is 537718.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.249 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00331 (494/149136) while in subpopulation EAS AF= 0.0389 (193/4960). AF 95% confidence interval is 0.0344. There are 8 homozygotes in gnomad4. There are 284 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAPSS2	NM_001015880.2	c.276T>C	p.Ser92=	synonymous_variant	3/13	ENST00000456849.2
PAPSS2	NM_004670.4	c.276T>C	p.Ser92=	synonymous_variant	3/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAPSS2	ENST00000456849.2	c.276T>C	p.Ser92=	synonymous_variant	3/13	1	NM_001015880.2	A1
PAPSS2	ENST00000361175.8	c.276T>C	p.Ser92=	synonymous_variant	3/12	1		P4
PAPSS2	ENST00000482258.1	n.319T>C		non_coding_transcript_exon_variant	3/3	5
PAPSS2	ENST00000465996.5			downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 481 AN: 149020 Hom.: 5 Cov.: 28

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000813

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0390

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.00290

Gnomad MID AF: 0.00662

Gnomad NFE AF: 0.000680

Gnomad OTH AF: 0.00439

GnomAD3 exomes AF: 0.00617 AC: 1550 AN: 251302 Hom.: 21 AF XY: 0.00692 AC XY: 940 AN XY: 135794

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0327

Gnomad SAS exome AF: 0.0228

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00326 AC: 4761 AN: 1460304 Hom.: 103 Cov.: 32 AF XY: 0.00386 AC XY: 2801 AN XY: 726496

Gnomad4 AFR exome AF: 0.00156

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0482

Gnomad4 SAS exome AF: 0.0209

Gnomad4 FIN exome AF: 0.00212

Gnomad4 NFE exome AF: 0.000519

Gnomad4 OTH exome AF: 0.00431

GnomAD4 genome AF: 0.00331 AC: 494 AN: 149136 Hom.: 8 Cov.: 28 AF XY: 0.00391 AC XY: 284 AN XY: 72658

Gnomad4 AFR AF: 0.00124

Gnomad4 AMR AF: 0.000813

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0389

Gnomad4 SAS AF: 0.0302

Gnomad4 FIN AF: 0.00290

Gnomad4 NFE AF: 0.000680

Gnomad4 OTH AF: 0.0106

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.00244

Asia WGS AF: 0.0370 AC: 129 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spondyloepimetaphyseal dysplasia, PAPSS2 type Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	7.7
Dann	Benign	0.66

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

LitVar

Other links and lift over

dbSNP: rs17124941; hg19: chr10-89472962; COSMIC: COSV63262919; COSMIC: COSV63262919;