10-87743553-C-T

Position:

• chr10-87743553-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001015880.2(PAPSS2):​c.1403C>T​(p.Ala468Val) variant causes a missense change. The variant allele was found at a frequency of 0.00066 in 1,614,084 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (4 hom.)
• Consequence: PAPSS2 NM_001015880.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 4.57

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013674557).
• BP6: Variant 10-87743553-C-T is Benign according to our data. Variant chr10-87743553-C-T is described in ClinVar as [Benign]. Clinvar id is 537719.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00215 (328/152246) while in subpopulation AFR AF= 0.00671 (279/41560). AF 95% confidence interval is 0.00607. There are 1 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAPSS2	NM_001015880.2	c.1403C>T	p.Ala468Val	missense_variant	11/13	ENST00000456849.2	NP_001015880.1
PAPSS2	NM_004670.4	c.1388C>T	p.Ala463Val	missense_variant	10/12		NP_004661.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAPSS2	ENST00000456849.2	c.1403C>T	p.Ala468Val	missense_variant	11/13	1	NM_001015880.2	ENSP00000406157.1
PAPSS2	ENST00000361175.8	c.1388C>T	p.Ala463Val	missense_variant	10/12	1		ENSP00000354436.4

Frequencies

GnomAD3 genomes AF: 0.00216 AC: 328 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00673

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00100 AC: 251 AN: 250714 Hom.: 0 AF XY: 0.000893 AC XY: 121 AN XY: 135534

Gnomad AFR exome AF: 0.00874

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00240

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.000345

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000504 AC: 737 AN: 1461838 Hom.: 4 Cov.: 33 AF XY: 0.000517 AC XY: 376 AN XY: 727218

Gnomad4 AFR exome AF: 0.00747

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00713

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.00215 AC: 328 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74432

Gnomad4 AFR AF: 0.00671

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00271

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.000620 Hom.: 0

Bravo AF: 0.00232

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00127 AC: 154

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Spondyloepimetaphyseal dysplasia, PAPSS2 type Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T;.
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.035
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.15
Sift	Benign	0.032	D;D
Sift4G	Benign	0.069	T;T
Polyphen		0.030	B;B
Vest4		0.63
MVP		0.36
MPC		0.23
ClinPred		0.021	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs34097979; hg19: chr10-89503310;