10-87709205-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001015880.2(PAPSS2):c.37C>G(p.Gln13Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAPSS2 NM_001015880.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13438854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAPSS2	NM_001015880.2	c.37C>G	p.Gln13Glu	missense_variant	2/13	ENST00000456849.2
PAPSS2	NM_004670.4	c.37C>G	p.Gln13Glu	missense_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAPSS2	ENST00000456849.2	c.37C>G	p.Gln13Glu	missense_variant	2/13	1	NM_001015880.2	A1
PAPSS2	ENST00000361175.8	c.37C>G	p.Gln13Glu	missense_variant	2/12	1		P4
PAPSS2	ENST00000465996.5	n.59C>G		non_coding_transcript_exon_variant	2/3	2
PAPSS2	ENST00000482258.1	n.80C>G		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spondyloepimetaphyseal dysplasia, PAPSS2 type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2021

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PAPSS2-related conditions. This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 13 of the PAPSS2 protein (p.Gln13Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.068
Eigen_PC	Benign	0.098
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.055
Sift	Benign	0.12	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0	B;B
Vest4		0.14
MutPred		0.31		Gain of ubiquitination at K14 (P = 0.0193);Gain of ubiquitination at K14 (P = 0.0193);
MVP		0.28
MPC		0.22
ClinPred		0.25	T
GERP RS		5.4
Varity_R		0.11
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-89468962;