rs185811230

Variant names:

• chr10-87659914-C-T
• rs185811230
• NM_001015880.2:c.-68C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001015880.2(PAPSS2):​c.-68C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 1,548,534 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (72 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (62 hom.)
• Consequence: PAPSS2 NM_001015880.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.144
• Publications: 0 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

ENSG00000196566 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 10-87659914-C-T is Benign according to our data. Variant chr10-87659914-C-T is described in ClinVar as [Benign]. Clinvar id is 1279508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAPSS2	NM_001015880.2	c.-68C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 13	ENST00000456849.2	NP_001015880.1
PAPSS2	NM_001015880.2	c.-68C>T		5_prime_UTR_variant	Exon 1 of 13	ENST00000456849.2	NP_001015880.1
PAPSS2	NM_004670.4	c.-68C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 12		NP_004661.2
PAPSS2	NM_004670.4	c.-68C>T		5_prime_UTR_variant	Exon 1 of 12		NP_004661.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAPSS2	ENST00000456849.2	c.-68C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 13	1	NM_001015880.2	ENSP00000406157.1
PAPSS2	ENST00000456849.2	c.-68C>T		5_prime_UTR_variant	Exon 1 of 13	1	NM_001015880.2	ENSP00000406157.1

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2440 AN: 148384 Hom.: 72 Cov.: 32

Gnomad AFR AF: 0.0607

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00531

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.0132

GnomAD4 exome AF: 0.00156 AC: 2191 AN: 1400038 Hom.: 62 Cov.: 27 AF XY: 0.00135 AC XY: 942 AN XY: 698474

African (AFR) AF: 0.0621 AC: 1803 AN: 29052

American (AMR) AF: 0.00277 AC: 121 AN: 43706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25532

East Asian (EAS) AF: 0.00 AC: 0 AN: 38956

South Asian (SAS) AF: 0.0000357 AC: 3 AN: 83960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50490

Middle Eastern (MID) AF: 0.00126 AC: 7 AN: 5572

European-Non Finnish (NFE) AF: 0.0000582 AC: 62 AN: 1064914

Other (OTH) AF: 0.00337 AC: 195 AN: 57856

GnomAD4 genome AF: 0.0165 AC: 2444 AN: 148496 Hom.: 72 Cov.: 32 AF XY: 0.0157 AC XY: 1137 AN XY: 72590

African (AFR) AF: 0.0606 AC: 2327 AN: 38368

American (AMR) AF: 0.00530 AC: 80 AN: 15088

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67750

Other (OTH) AF: 0.0130 AC: 27 AN: 2072

Alfa AF: 0.0153 Hom.: 6

Bravo AF: 0.0185

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 14, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.5
DANN	Benign	0.95
PhyloP100		-0.14
PromoterAI		-0.026	Neutral
Mutation Taster		=300/0	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: rs185811230; hg19: chr10-89419671;