NM_001015880.2:c.1403C>A

Variant names:

• chr10-87743553-C-A
• rs34097979
• NM_001015880.2:c.1403C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001015880.2(PAPSS2):​c.1403C>A​(p.Ala468Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A468T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAPSS2 NM_001015880.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.57
• Publications: 6 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38268602).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPSS2	NM_001015880.2	c.1403C>A	p.Ala468Glu	missense_variant	Exon 11 of 13	ENST00000456849.2	NP_001015880.1
PAPSS2	NM_004670.4	c.1388C>A	p.Ala463Glu	missense_variant	Exon 10 of 12		NP_004661.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPSS2	ENST00000456849.2	c.1403C>A	p.Ala468Glu	missense_variant	Exon 11 of 13	1	NM_001015880.2	ENSP00000406157.1
PAPSS2	ENST00000361175.8	c.1388C>A	p.Ala463Glu	missense_variant	Exon 10 of 12	1		ENSP00000354436.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.80
DEOGEN2	Benign	0.030	T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.020	N;.
PhyloP100		4.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	1.4	N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;B
Vest4		0.65
MutPred		0.57		Gain of ubiquitination at K460 (P = 0.0499);.;
MVP		0.28
MPC		0.35
ClinPred		0.31	T
GERP RS		5.3
Varity_R		0.13
gMVP		0.78
Mutation Taster		=75/25	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: rs34097979; hg19: chr10-89503310;