rs1555198165

Positions:

• chr11-112229366-TGTAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGA-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_000317.3(PTS):​c.163+696_163+750delAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGAGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTS NM_000317.3 intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.06

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112229366-TGTAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGA-T is Pathogenic according to our data. Variant chr11-112229366-TGTAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 485.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-112229366-TGTAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTS	NM_000317.3	c.163+696_163+750delAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGAGT		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+696_163+750delAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGAGT		intron_variant		1	NM_000317.3	ENSP00000280362.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 17, 2022	Variant summary: PTS c.163+696_163+750del55 is located at a deep intronic position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a cryptic 3' acceptor site, while four predict the variant strengthens a cryptic 3' acceptor site. The variant was absent in 150906 control chromosomes (gnomAD v3.1, genomes dataset). The variant c.163+696_163+750del55 (aka g.3760_3816del55) has been reported in the literature in individuals affected with 6-Pyruvoyl-Tetrahydropterin Synthase Deficiency, who carried a pathogenic variant in trans (Meili_2009, Manti_2020, Manzoni_2020). These data indicate that the variant may be associated with disease. Publications also reported experimental evidence, and generation of a pseudoexon was demonstrated from patient derived mRNA and in mini-gene assay systems (Meili_2009, Brasil_2011), together with the absence of protein product in patient derived fibroblasts (Meili_2009). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555198165; hg19: chr11-112100089;