rs1555198165

Variant names:

• chr11-112229366-TGTAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGA-T
• rs1555198165
• NM_000317.3:c.163+696_163+750delAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGAGT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS3 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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV002547969: 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).".

• 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
• 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002547969: 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).
• PP5: Variant 11-112229366-TGTAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGA-T is Pathogenic according to our data. Variant chr11-112229366-TGTAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 485.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000317.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTS	NM_000317.3	MANE Select	c.163+696_163+750delAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGAGT		intron	N/A	NP_000308.1	Q03393

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTS	ENST00000280362.8	TSL:1 MANE Select	c.163+696_163+750delAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGAGT		intron	N/A	ENSP00000280362.3	Q03393
	PTS	ENST00000525645.1	TSL:1	n.934_988delAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGAGT		non_coding_transcript_exon	Exon 2 of 2
	PTS	ENST00000531673.5	TSL:1	n.163+696_163+750delAAAGCACTGATAAAGTTTTTTTTTGTTGTTGTTGTTTTTTTTTTTGAGATGGAGT		intron	N/A	ENSP00000433469.1	E9PKY8

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555198165; hg19: chr11-112100089;