Variant 11-112226501-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000317.3(PTS):c.58T>C(p.Phe20Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000697 in 1,433,716 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

PTS
NM_000317.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.01

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTS	NM_000317.3 linkuse as main transcript	c.58T>C	p.Phe20Leu	missense_variant	1/6	ENST00000280362.8	NP_000308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTS	ENST00000280362.8 linkuse as main transcript	c.58T>C	p.Phe20Leu	missense_variant	1/6	1	NM_000317.3	ENSP00000280362	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.97e-7

AC:

AN:

1433716

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

710194

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000258

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 08, 2024

Variant summary: PTS c.58T>C (p.Phe20Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 201782 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.58T>C has been reported in the literature in individuals suspected with 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency without informative genotypes (example: Chiu_2012). These report(s) do not provide unequivocal conclusions about association of the variant with 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22237589). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.4

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-4.2

D;D

REVEL

Pathogenic

0.92

Sift

Benign

0.032

D;D

Sift4G

Uncertain

0.047

D;D

Polyphen

0.98

D;.

Vest4

0.92

MutPred

0.88

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);

MVP

1.0

MPC

0.90

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over