rs3819331

Positions:

• chr11-112228687-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000317.3(PTS):​c.163+14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,600,344 control chromosomes in the GnomAD database, including 21,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1451 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19881 hom.)
• Consequence: PTS NM_000317.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.186

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 11-112228687-T-C is Benign according to our data. Variant chr11-112228687-T-C is described in ClinVar as [Benign]. Clinvar id is 302498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112228687-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTS	NM_000317.3	c.163+14T>C		intron_variant		ENST00000280362.8	NP_000308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTS	ENST00000280362.8	c.163+14T>C		intron_variant		1	NM_000317.3	ENSP00000280362	P1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18147 AN: 151806 Hom.: 1445 Cov.: 32

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.129

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.112

GnomAD3 exomes AF: 0.166 AC: 41463 AN: 249736 Hom.: 4306 AF XY: 0.174 AC XY: 23554 AN XY: 135122

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.130

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.262

Gnomad SAS exome AF: 0.323

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.155 AC: 224757 AN: 1448424 Hom.: 19881 Cov.: 30 AF XY: 0.160 AC XY: 115644 AN XY: 721378

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.129

Gnomad4 ASJ exome AF: 0.136

Gnomad4 EAS exome AF: 0.225

Gnomad4 SAS exome AF: 0.320

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.146

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.120 AC: 18160 AN: 151920 Hom.: 1451 Cov.: 32 AF XY: 0.124 AC XY: 9224 AN XY: 74234

Gnomad4 AFR AF: 0.0282

Gnomad4 AMR AF: 0.127

Gnomad4 ASJ AF: 0.129

Gnomad4 EAS AF: 0.258

Gnomad4 SAS AF: 0.344

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.144

Gnomad4 OTH AF: 0.118

Alfa AF: 0.140 Hom.: 2450

Bravo AF: 0.110

Asia WGS AF: 0.281 AC: 978 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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	-0.85
CADD	Benign	9.5
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs3819331; hg19: chr11-112099410; COSMIC: COSV54785665; COSMIC: COSV54785665;