rs5030852

Positions:

• chr12-102852814-C-A
• chr12-102852814-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4 PVS1 PM2

This summary comes from the ClinGen Evidence Repository: The PAH c.842+1G>T variant has been reported at least once in the literature in a 15 month old patient with moderate PKU in the homozygote state (PP4, PMID:23220018). This variant is absent from 1000G, ESP, and gnomAD databases. This variant disrupts the canonical splice donor site of intron 7 where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 7 is present in biologically-relevant transcript. In summary, this variant meets criteria to be pathogenic. PAH-specific ACMG/AMP criteria applied: PM2, PP4, PVS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229812/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:1 O:1
• Conservation: PhyloP100: 7.91

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: 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.842+1G>T		splice_donor_variant		ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.842+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.842+1G>T		splice_donor_variant		1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000307000.7	c.827+1G>T		splice_donor_variant		5		ENSP00000303500
PAH	ENST00000635477.1	c.3+1G>T		splice_donor_variant		5		ENSP00000489230
PAH	ENST00000549247.6	n.601+1G>T		splice_donor_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen PAH Variant Curation Expert Panel

Apr 09, 2019

The PAH c.842+1G>T variant has been reported at least once in the literature in a 15 month old patient with moderate PKU in the homozygote state (PP4, PMID: 23220018). This variant is absent from 1000G, ESP, and gnomAD databases. This variant disrupts the canonical splice donor site of intron 7 where LOF is a known mechanism of disease, exon skipping disrupts reading frame, and is predicted to undergo NMD. Coding exon 7 is present in biologically-relevant transcript. In summary, this variant meets criteria to be pathogenic. PAH-specific ACMG/AMP criteria applied: PM2, PP4, PVS1. -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs5030852; hg19: chr12-103246592;