10-87659881-CGCTGCTGCTGCT-CGCTGCTGCT

Variant names:

• chr10-87659881-CGCT-C
• rs3217087
• NM_001015880.2:c.-77_-75delTGC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001015880.2(PAPSS2):​c.-77_-75delTGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,017,966 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00021 (1 hom., cov: 0)
  • Exomes 𝑓: 0.0027 (0 hom.)
• Consequence: PAPSS2 NM_001015880.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.779
• 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive brachyolmia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000196566 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000205 (31/151154) while in subpopulation AMR AF = 0.00158 (24/15204). AF 95% confidence interval is 0.00109. There are 1 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001015880.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPSS2	NM_001015880.2	MANE Select	c.-77_-75delTGC		5_prime_UTR	Exon 1 of 13	NP_001015880.1	O95340-2
	PAPSS2	NM_004670.4		c.-77_-75delTGC		5_prime_UTR	Exon 1 of 12	NP_004661.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPSS2	ENST00000456849.2	TSL:1 MANE Select	c.-77_-75delTGC		5_prime_UTR	Exon 1 of 13	ENSP00000406157.1	O95340-2
	PAPSS2	ENST00000361175.8	TSL:1	c.-77_-75delTGC		5_prime_UTR	Exon 1 of 12	ENSP00000354436.4	O95340-1
	PAPSS2	ENST00000904622.1		c.-77_-75delTGC		5_prime_UTR	Exon 1 of 13	ENSP00000574681.1

Frequencies

GnomAD3 genomes AF: 0.000205 AC: 31 AN: 151050 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000740

Gnomad OTH AF: 0.000486

GnomAD4 exome AF: 0.00271 AC: 2351 AN: 866812 Hom.: 0 AF XY: 0.00254 AC XY: 1141 AN XY: 449938

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00200 AC: 43 AN: 21538

American (AMR) AF: 0.00209 AC: 80 AN: 38338

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 25 AN: 21376

East Asian (EAS) AF: 0.00285 AC: 92 AN: 32294

South Asian (SAS) AF: 0.00160 AC: 112 AN: 69790

European-Finnish (FIN) AF: 0.00243 AC: 110 AN: 45260

Middle Eastern (MID) AF: 0.00230 AC: 10 AN: 4354

European-Non Finnish (NFE) AF: 0.00299 AC: 1777 AN: 593796

Other (OTH) AF: 0.00255 AC: 102 AN: 40066

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000205 AC: 31 AN: 151154 Hom.: 1 Cov.: 0 AF XY: 0.000244 AC XY: 18 AN XY: 73864

African (AFR) AF: 0.0000243 AC: 1 AN: 41234

American (AMR) AF: 0.00158 AC: 24 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000740 AC: 5 AN: 67602

Other (OTH) AF: 0.000481 AC: 1 AN: 2080

Alfa AF: 0.00 Hom.: 286

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.78
Mutation Taster		=298/2	polymorphism

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

Other links and lift over

dbSNP: rs3217087; hg19: chr10-89419638;