rs5030861

Positions:

• chr12-102840399-C-A
• chr12-102840399-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP4

This summary comes from the ClinGen Evidence Repository: The c.1315+1G>T variant in PAH is a canonical splice-site variant predicted to lead to skipping of exon 13 (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.It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2).The variant has been previously reported in one Catalonian PKU case (as determined by abnormal blood Phe levels), without additional information (PMID:10598814) (PP4). It is also noted in ClinVar (ID 370074), where it is classified as Likely Pathogenic by one lab, with this published reported cited. Classification: Likely PathogenicSupporting Criteria: PVS1_Strong; PM2; PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020993/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAH ENST00000553106.6 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 7.46

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.1315+1G>T		splice_donor_variant		ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1315+1G>T		splice_donor_variant			NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1315+1G>T		splice_donor_variant		1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 27, 2015	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	May 18, 2020	The c.1315+1G>T variant in PAH is a canonical splice-site variant predicted to lead to skipping of exon 13 (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. It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). The variant has been previously reported in one Catalonian PKU case (as determined by abnormal blood Phe levels), without additional information (PMID: 10598814) (PP4). It is also noted in ClinVar (ID 370074), where it is classified as Likely Pathogenic by one lab, with this published reported cited. Classification: Likely Pathogenic Supporting Criteria: PVS1_Strong; PM2; PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.94		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs5030861; hg19: chr12-103234177; COSMIC: COSV61017004; COSMIC: COSV61017004;