chr10-87709196-G-A

Variant names:

• chr10-87709196-G-A
• rs17173698
• NM_001015880.2:c.28G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001015880.2(PAPSS2):​c.28G>A​(p.Glu10Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0193 in 1,599,836 control chromosomes in the GnomAD database, including 370 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (17 hom., cov: 32)
  • Exomes 𝑓: 0.020 (353 hom.)
• Consequence: PAPSS2 NM_001015880.2 missense, splice_region
• Scores: Splicing: ADA: 0.9972
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.10
• Publications: 16 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: Benign. The variant received -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 10-87709196-G-A is Benign according to our data. Variant chr10-87709196-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 288334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0131 (1999/152188) while in subpopulation NFE AF = 0.0211 (1432/67992). AF 95% confidence interval is 0.0202. There are 17 homozygotes in GnomAd4. There are 911 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPSS2	NM_001015880.2	MANE Select	c.28G>A	p.Glu10Lys	missense splice_region	Exon 2 of 13	NP_001015880.1
	PAPSS2	NM_004670.4		c.28G>A	p.Glu10Lys	missense splice_region	Exon 2 of 12	NP_004661.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAPSS2	ENST00000456849.2	TSL:1 MANE Select	c.28G>A	p.Glu10Lys	missense splice_region	Exon 2 of 13	ENSP00000406157.1
	PAPSS2	ENST00000361175.8	TSL:1	c.28G>A	p.Glu10Lys	missense splice_region	Exon 2 of 12	ENSP00000354436.4
	PAPSS2	ENST00000465996.5	TSL:2	n.50G>A		splice_region non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2002 AN: 152070 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00331

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0123

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.00863

GnomAD2 exomes AF: 0.0133 AC: 3343 AN: 251322 AF XY: 0.0134

Gnomad AFR exome AF: 0.00344

Gnomad AMR exome AF: 0.00804

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.0212

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0200 AC: 28898 AN: 1447648 Hom.: 353 Cov.: 28 AF XY: 0.0193 AC XY: 13948 AN XY: 721230

African (AFR) AF: 0.00286 AC: 95 AN: 33190

American (AMR) AF: 0.00890 AC: 398 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0232 AC: 604 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39590

South Asian (SAS) AF: 0.00192 AC: 165 AN: 85946

European-Finnish (FIN) AF: 0.0118 AC: 629 AN: 53266

Middle Eastern (MID) AF: 0.00366 AC: 21 AN: 5734

European-Non Finnish (NFE) AF: 0.0237 AC: 26031 AN: 1099360

Other (OTH) AF: 0.0160 AC: 955 AN: 59864

GnomAD4 genome AF: 0.0131 AC: 1999 AN: 152188 Hom.: 17 Cov.: 32 AF XY: 0.0122 AC XY: 911 AN XY: 74408

African (AFR) AF: 0.00330 AC: 137 AN: 41540

American (AMR) AF: 0.0122 AC: 186 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 81 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00146 AC: 7 AN: 4810

European-Finnish (FIN) AF: 0.0129 AC: 137 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1432 AN: 67992

Other (OTH) AF: 0.00854 AC: 18 AN: 2108

Alfa AF: 0.0176 Hom.: 48

Bravo AF: 0.0130

TwinsUK AF: 0.0218 AC: 81

ALSPAC AF: 0.0275 AC: 106

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0215 AC: 185

ExAC AF: 0.0138 AC: 1679

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.0182

EpiControl AF: 0.0190

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	Spondyloepimetaphyseal dysplasia, PAPSS2 type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.086
Sift	Benign	0.25	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.15
MPC		0.23
ClinPred		0.019	T
GERP RS		4.8
Varity_R		0.11
gMVP		0.54
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.13		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: rs17173698; hg19: chr10-89468953; COSMIC: COSV63263743;