10-87659881-CGCTGCTGCTGCT-CGCTGCTGCTGCTGCTGCTGCTGCT

Variant names:

• chr10-87659881-C-CGCTGCTGCTGCT
• rs3217087
• NM_001015880.2:c.-86_-75dupTGCTGCTGCTGC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001015880.2(PAPSS2):​c.-86_-75dupTGCTGCTGCTGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (28 hom., cov: 0)
  • Exomes 𝑓: 0.0058 (18 hom.)
• Consequence: PAPSS2 NM_001015880.2 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0360
• Publications: 2 publications found

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

ENSG00000196566 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 10-87659881-C-CGCTGCTGCTGCT is Benign according to our data. Variant chr10-87659881-C-CGCTGCTGCTGCT is described in ClinVar as [Likely_benign]. Clinvar id is 1326444.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0156 (2353/151154) while in subpopulation AFR AF = 0.0403 (1663/41224). AF 95% confidence interval is 0.0387. There are 28 homozygotes in GnomAd4. There are 1108 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPSS2	NM_001015880.2	c.-86_-75dupTGCTGCTGCTGC		5_prime_UTR_variant	Exon 1 of 13	ENST00000456849.2	NP_001015880.1
PAPSS2	NM_004670.4	c.-86_-75dupTGCTGCTGCTGC		5_prime_UTR_variant	Exon 1 of 12		NP_004661.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPSS2	ENST00000456849.2	c.-86_-75dupTGCTGCTGCTGC		5_prime_UTR_variant	Exon 1 of 13	1	NM_001015880.2	ENSP00000406157.1

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2349 AN: 151050 Hom.: 28 Cov.: 0

Gnomad AFR AF: 0.0403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00839

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00333

Gnomad FIN AF: 0.00325

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.00572

Gnomad OTH AF: 0.0170

GnomAD4 exome AF: 0.00576 AC: 5104 AN: 886518 Hom.: 18 Cov.: 14 AF XY: 0.00569 AC XY: 2617 AN XY: 460142

African (AFR) AF: 0.0362 AC: 794 AN: 21934

American (AMR) AF: 0.00799 AC: 315 AN: 39416

Ashkenazi Jewish (ASJ) AF: 0.00820 AC: 180 AN: 21944

East Asian (EAS) AF: 0.000115 AC: 4 AN: 34844

South Asian (SAS) AF: 0.00383 AC: 276 AN: 72020

European-Finnish (FIN) AF: 0.00248 AC: 116 AN: 46760

Middle Eastern (MID) AF: 0.0160 AC: 71 AN: 4434

European-Non Finnish (NFE) AF: 0.00487 AC: 2943 AN: 604086

Other (OTH) AF: 0.00986 AC: 405 AN: 41080

GnomAD4 genome AF: 0.0156 AC: 2353 AN: 151154 Hom.: 28 Cov.: 0 AF XY: 0.0150 AC XY: 1108 AN XY: 73870

African (AFR) AF: 0.0403 AC: 1663 AN: 41224

American (AMR) AF: 0.0119 AC: 181 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00839 AC: 29 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00292 AC: 14 AN: 4800

European-Finnish (FIN) AF: 0.00325 AC: 34 AN: 10462

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.00572 AC: 387 AN: 67600

Other (OTH) AF: 0.0168 AC: 35 AN: 2080

Alfa AF: 0.000969 Hom.: 286

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 24, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.036
Mutation Taster		=300/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3217087; hg19: chr10-89419638;