NM_000317.3:c.393delA

Variant names:

• chr11-112233506-TA-T
• rs780332520
• NM_000317.3:c.393delA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000317.3(PTS):​c.393delA​(p.Val132TyrfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,386 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K131K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PTS NM_000317.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.0730
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• BH4-deficient hyperphenylalaninemia A

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112233506-TA-T is Pathogenic according to our data. Variant chr11-112233506-TA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 556173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTS	NM_000317.3	c.393delA	p.Val132TyrfsTer19	frameshift_variant	Exon 6 of 6	ENST00000280362.8	NP_000308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTS	ENST00000280362.8	c.393delA	p.Val132TyrfsTer19	frameshift_variant	Exon 6 of 6	1	NM_000317.3	ENSP00000280362.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000160 AC: 4 AN: 250742 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461386 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726976

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.0000671 AC: 3 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111776

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:5

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change results in a frameshift in the PTS gene (p.Val132Tyrfs*19). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the PTS protein and extend the protein by 4 additional amino acid residues. This variant is present in population databases (rs780332520, gnomAD 0.006%). This frameshift has been observed in individual(s) with biopterin-deficient hyperphenylalaninemia (PMID: 19280650, 20059486). ClinVar contains an entry for this variant (Variation ID: 556173). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Jan 16, 2018

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 13, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.073
Mutation Taster		=5/195	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs780332520; hg19: chr11-112104229;