rs189365250

chr11-112233429-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000317.3(PTS):c.315-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,609,882 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (22 hom.)
• Consequence: PTS NM_000317.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004008
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.547

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=-0.49).
• BP6: Variant 11-112233429-T-C is Benign according to our data. Variant chr11-112233429-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 532010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112233429-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00414 (631/152306) while in subpopulation AMR AF= 0.00627 (96/15302). AF 95% confidence interval is 0.00526. There are 2 homozygotes in gnomad4. There are 322 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTS	NM_000317.3	c.315-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000280362.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTS	ENST00000280362.8	c.315-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000317.3	P1

Frequencies

GnomAD3 genomes AF: 0.00415 AC: 632 AN: 152188 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0131

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00492

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00356 AC: 877 AN: 246582 Hom.: 4 AF XY: 0.00337 AC XY: 451 AN XY: 133738

Gnomad AFR exome AF: 0.000778

Gnomad AMR exome AF: 0.00305

Gnomad ASJ exome AF: 0.00201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000271

Gnomad FIN exome AF: 0.0120

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00317

GnomAD4 exome AF: 0.00452 AC: 6587 AN: 1457576 Hom.: 22 Cov.: 31 AF XY: 0.00435 AC XY: 3150 AN XY: 724686

Gnomad4 AFR exome AF: 0.000872

Gnomad4 AMR exome AF: 0.00328

Gnomad4 ASJ exome AF: 0.00219

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000283

Gnomad4 FIN exome AF: 0.0120

Gnomad4 NFE exome AF: 0.00493

Gnomad4 OTH exome AF: 0.00359

GnomAD4 genome AF: 0.00414 AC: 631 AN: 152306 Hom.: 2 Cov.: 32 AF XY: 0.00432 AC XY: 322 AN XY: 74480

Gnomad4 AFR AF: 0.000963

Gnomad4 AMR AF: 0.00627

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0131

Gnomad4 NFE AF: 0.00491

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00418 Hom.: 0

Bravo AF: 0.00313

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00355

EpiControl AF: 0.00285

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	PTS: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	8.5
Dann	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.022
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: rs189365250; hg19: chr11-112104152;