rs1334974448

chr12-102840395-CTTACTG-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_Moderate PP3 PP5_Very_Strong

The NM_000277.3(PAH):c.1314_1315+4del variant causes a splice donor, splice donor region, coding sequence, intron change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 splice_donor, splice_donor_region, coding_sequence, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 8.81

Genes affected

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates 0.0331125827814569 fraction of the geneNo cryptic splice site detected. Exon removal results in frameshift change.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 12-102840395-CTTACTG-C is Pathogenic according to our data. Variant chr12-102840395-CTTACTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 555797.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102840395-CTTACTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.1314_1315+4del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	12/13	ENST00000553106.6
PAH	NM_001354304.2	c.1314_1315+4del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	13/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.1314_1315+4del		splice_donor_variant, splice_donor_region_variant, coding_sequence_variant, intron_variant	12/13	1	NM_000277.3	P1

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

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	May 21, 2020	The c.1314_1315+4del6 (p.N438fs) variant is a frameshift variant in exon 12 of 13 of a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1_Strong). Exon 13 encodes 15 amino acids + stop codon = 3.3% of PAH protein length. Along with Exon 12, Exon 13 forms the oligomerization domain (residues 411-452), which is responsible for the dimerization and tetramerization of the enzyme, important for regulation of PAH activity (e.g., positive cooperativity by the substrate, L-Phe, and decreasing PAH activity at low L-Phe concentration) (see PMID: 23457044; PMID: 22005392). Exon 13 contains the non-truncating Likely Pathogenic p.A447P (Likely Pathogenic by ClinGen PAH VCEP) and Pathogenic p.A447D variants (Likely Pathogenic by ClinGen PAH VCEP; Pathogenic in Clinvar (ID 102595; 4 submitters, 2 stars). Thus PVS1_Strong will be applied for variants resulting in deletion of this exon. The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is listed in ClinVar (variant ID 555797) as Likely Pathogenic by one lab. It has been reported in the published literature in one case (PMID: 23514811) with abnormal blood Phe and BH4 deficiency formally excluded (PP4_Moderate); in trans with the p.R138Q variant (Pathogenic per PAH VCEP) (PM3). Classification: Pathogenic Supporting Criteria: PVS1_Strong; PM2; PM3; PP4_Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 21, 2017	- -

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: rs1334974448; hg19: chr12-103234173;