rs797045099

Positions:

• chr10-87745165-TCATTC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001015880.2(PAPSS2):​c.1662_1666delATTCC​(p.Phe555fs) 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 (★). 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

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 Pathogenic. Variant got 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 id is 208601.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAPSS2	NM_001015880.2	c.1662_1666delATTCC	p.Phe555fs	frameshift_variant	12/13	ENST00000456849.2	NP_001015880.1
PAPSS2	NM_004670.4	c.1647_1651delATTCC	p.Phe550fs	frameshift_variant	11/12		NP_004661.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAPSS2	ENST00000456849.2	c.1662_1666delATTCC	p.Phe555fs	frameshift_variant	12/13	1	NM_001015880.2	ENSP00000406157.1
PAPSS2	ENST00000361175.8	c.1647_1651delATTCC	p.Phe550fs	frameshift_variant	11/12	1		ENSP00000354436.4

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

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spondyloepimetaphyseal dysplasia, PAPSS2 type Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 04, 2015

The p.Phe555serfsX15 variant in PAPSS2 has not been previously reported in individuals with brachyolmia and was absent in large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 555 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Complete loss of PAPSS2 function has been identified in many individuals with brachyolmia (Faiyaz ul Haque 1998, Noordam 2009, Miyake 2012, Tuysuz 2013, Iida 2013), though all previously reported loss-of-function variants reside upstream of this variant. In summary, although additional studies are required to fully establish its clinical significance, the p.Phe555SerfsX15 variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs797045099; hg19: chr10-89504922;