rs747260038

Positions:

• chr11-112228625-CTGTT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000317.3(PTS):​c.118_121del​(p.Phe40GlyfsTer17) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000439 in 1,595,816 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PTS NM_000317.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.17

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112228625-CTGTT-C is Pathogenic according to our data. Variant chr11-112228625-CTGTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 550850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTS	NM_000317.3	c.118_121del	p.Phe40GlyfsTer17	frameshift_variant	2/6	ENST00000280362.8	NP_000308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTS	ENST00000280362.8	c.118_121del	p.Phe40GlyfsTer17	frameshift_variant	2/6	1	NM_000317.3	ENSP00000280362	P1

Frequencies

GnomAD3 genomes AF: 0.00000682 AC: 1 AN: 146526 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000200

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: 0.00000404 AC: 1 AN: 247390 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134032

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: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1449290 Hom.: 0 AF XY: 0.00000555 AC XY: 4 AN XY: 721200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000452

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000682 AC: 1 AN: 146526 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 70864

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000200

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change creates a premature translational stop signal (p.Phe40Glyfs*17) in the PTS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTS are known to be pathogenic (PMID: 3297709, 16917893). This variant is present in population databases (rs747260038, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with 6-pyruvoyl-tetrahydropterin synthase deficiency (PMID: 23138986). ClinVar contains an entry for this variant (Variation ID: 550850). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2018

The c.118_121delTTTG variant in the PTS gene has been reported previously using alternate nomenclature (c.116_119del) in a heterozygous individual with mild hyperphenylalaninemia and no identifiable second variant (Liu et al., 2001). The variant has also been reported in a female infant with PTPSD who harbored a second PTS variant (Ye et al., 2013). The c.118_121delTTTG variant causes a frameshift starting with codon Phenylalanine 40, changes this amino acid to a Glycine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Phe40GlyfsX17. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.118_121delTTTG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.118_121delTTTG as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs747260038; hg19: chr11-112099348;