rs59731976

Positions:

• chr11-112233522-T-C
• chr11-112233522-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000317.3(PTS):​c.405T>C​(p.Thr135=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,613,636 control chromosomes in the GnomAD database, including 514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (255 hom., cov: 32)
  • Exomes 𝑓: 0.010 (259 hom.)
• Consequence: PTS NM_000317.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.408

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 11-112233522-T-C is Benign according to our data. Variant chr11-112233522-T-C is described in ClinVar as [Benign]. Clinvar id is 302499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112233522-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.408 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTS	NM_000317.3	c.405T>C	p.Thr135=	synonymous_variant	6/6	ENST00000280362.8	NP_000308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTS	ENST00000280362.8	c.405T>C	p.Thr135=	synonymous_variant	6/6	1	NM_000317.3	ENSP00000280362	P1

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5519 AN: 152114 Hom.: 256 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00750

Gnomad OTH AF: 0.0283

GnomAD3 exomes AF: 0.0138 AC: 3459 AN: 250774 Hom.: 106 AF XY: 0.0119 AC XY: 1621 AN XY: 135750

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00177

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00833

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0103 AC: 15114 AN: 1461404 Hom.: 259 Cov.: 31 AF XY: 0.00963 AC XY: 6998 AN XY: 727018

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.0147

Gnomad4 ASJ exome AF: 0.00965

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00166

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.00832

Gnomad4 OTH exome AF: 0.0140

GnomAD4 genome AF: 0.0364 AC: 5537 AN: 152232 Hom.: 255 Cov.: 32 AF XY: 0.0343 AC XY: 2554 AN XY: 74446

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0214

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00751

Gnomad4 OTH AF: 0.0280

Alfa AF: 0.0145 Hom.: 32

Bravo AF: 0.0403

Asia WGS AF: 0.00751 AC: 26 AN: 3474

EpiCase AF: 0.00977

EpiControl AF: 0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 22, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PTS-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.4
DANN	Benign	0.79

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: rs59731976; hg19: chr11-112104245;