chr11-112230201-T-A

Variant names:

• chr11-112230201-T-A
• rs1555198232
• NM_000317.3:c.164-7T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PS3 PM2 PP5_Moderate BP4

The NM_000317.3(PTS):​c.164-7T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV002162421: RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that this variant is associated with skipping of exon 3, which introduces a premature termination codon (PMID:7493990, 8841415).".

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTS NM_000317.3 splice_region, intron
• Scores: Splicing: ADA: 0.004857
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 0.189
• Publications: 0 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 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002162421: RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that this variant is associated with skipping of exon 3, which introduces a premature termination codon (PMID: 7493990, 8841415).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-112230201-T-A is Pathogenic according to our data. Variant chr11-112230201-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 552046.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38). . Strength limited to SUPPORTING due to the PP5.

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.164-7T>A		splice_region 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.164-7T>A		splice_region intron	N/A	ENSP00000280362.3	Q03393
	PTS	ENST00000531673.5	TSL:1	n.164-425T>A		intron	N/A	ENSP00000433469.1	E9PKY8
	PTS	ENST00000889305.1		c.164-7T>A		splice_region intron	N/A	ENSP00000559364.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	1	-	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.83
PhyloP100		0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0049
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.20		Position offset: 7

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

Other links and lift over

dbSNP: rs1555198232; hg19: chr11-112100924;