rs374871539

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_000317.3(PTS):c.95G>A(p.Ser32Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000694 in 1,584,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

PTS
NM_000317.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 3.86

Variant links:

Genes affected

PTS (HGNC:9689): (6-pyruvoyltetrahydropterin synthase) The enzyme encoded by this gene catalyzes the elimination of inorganic triphosphate from dihydroneopterin triphosphate, which is the second and irreversible step in the biosynthesis of tetrahydrobiopterin from GTP. Tetrahydrobiopterin, also known as BH(4), is an essential cofactor and regulator of various enzyme activities, including enzymes involved in serotonin biosynthesis and NO synthase activity. Mutations in this gene result in hyperphenylalaninemia. [provided by RefSeq, Oct 2008]

PTS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a chain 6-pyruvoyl tetrahydrobiopterin synthase (size 144) in uniprot entity PTPS_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000317.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

PP5

Variant 11-112228605-G-A is Pathogenic according to our data. Variant chr11-112228605-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 463155.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTS	NM_000317.3 link	c.95G>A	p.Ser32Asn	missense_variant	Exon 2 of 6	ENST00000280362.8	NP_000308.1	Q03393

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTS	ENST00000280362.8 link	c.95G>A	p.Ser32Asn	missense_variant	Exon 2 of 6	1	NM_000317.3	ENSP00000280362.3		Q03393

Frequencies

GnomAD3 genomes

AF:

0.00000673

AC:

AN:

148562

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000841

AC:

AN:

237908

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

129254

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000697

AC:

AN:

1435628

Hom.:

Cov.:

AF XY:

0.00000979

AC XY:

AN XY:

714852

show subpopulations

Gnomad4 AFR exome

AF:

0.000122

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000182

Gnomad4 OTH exome

AF:

0.0000504

GnomAD4 genome

AF:

0.00000673

AC:

AN:

148562

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

72138

show subpopulations

Gnomad4 AFR

AF:

0.0000249

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency

Pathogenic:1Uncertain:1

Nov 11, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 32 of the PTS protein (p.Ser32Asn). This variant is present in population databases (rs374871539, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of PTS-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 463155). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. This variant disrupts the p.Ser32 amino acid residue in PTS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31332730, 33822819; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Uncertain:1

Aug 19, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.92

D;.

Eigen

Benign

0.0044

Eigen_PC

Benign

-0.061

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

T;T

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.0

N;D

REVEL

Uncertain

0.57

Sift

Benign

0.045

D;D

Sift4G

Benign

0.061

T;D

Polyphen

0.74

P;.

Vest4

0.59

MutPred

0.54

Loss of phosphorylation at S32 (P = 0.0457);Loss of phosphorylation at S32 (P = 0.0457);

MVP

0.98

MPC

0.31

ClinPred

0.61

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.39

gMVP

0.78

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over