rs797045099

Variant names:

• chr10-87745165-TCATTC-T
• rs797045099
• NM_001015880.2:c.1662_1666delATTCC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001015880.2(PAPSS2):​c.1662_1666delATTCC​(p.Phe555SerfsTer15) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P554P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAPSS2 NM_001015880.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67
• Publications: 0 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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-87745165-TCATTC-T is Pathogenic according to our data. Variant chr10-87745165-TCATTC-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 208601.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1662_1666delATTCC	p.Phe555SerfsTer15	frameshift	Exon 12 of 13	NP_001015880.1	O95340-2
	PAPSS2	NM_004670.4		c.1647_1651delATTCC	p.Phe550SerfsTer15	frameshift	Exon 11 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.1662_1666delATTCC	p.Phe555SerfsTer15	frameshift	Exon 12 of 13	ENSP00000406157.1	O95340-2
	PAPSS2	ENST00000361175.8	TSL:1	c.1647_1651delATTCC	p.Phe550SerfsTer15	frameshift	Exon 11 of 12	ENSP00000354436.4	O95340-1
	PAPSS2	ENST00000904622.1		c.1716_1720delATTCC	p.Phe573SerfsTer15	frameshift	Exon 12 of 13	ENSP00000574681.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Spondyloepimetaphyseal dysplasia, PAPSS2 type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7

Splicing

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

Other links and lift over

dbSNP: rs797045099; hg19: chr10-89504922;