12-102866607-G-T

Position:

• chr12-102866607-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP4 PM3 PVS1 PM2

This summary comes from the ClinGen Evidence Repository: The c.498C>A (p.Tyr166Ter) variant in PAH is a nonsense variant in exon 5 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in individuals with Classic PKU in German and Chinese cohorts. (PP4, PMID:16256386; 10394930). This variant is absent from ExAC/gnomAD, 1000 Genomes, and ESP (PM2). This variant was detected with multiple known pathogenic variants (PM3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229583/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:1 O:1
• Conservation: PhyloP100: 1.46

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]

LOC124902999 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 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.
• PM3: 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.498C>A	p.Tyr166Ter	stop_gained	5/13	ENST00000553106.6	NP_000268.1
LOC124902999	XR_007063428.1	n.807+1380G>T		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.498C>A	p.Tyr166Ter	stop_gained	6/14		NP_001341233.1
PAH	XM_017019370.2	c.498C>A	p.Tyr166Ter	stop_gained	5/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.498C>A	p.Tyr166Ter	stop_gained	5/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000549111.5	n.594C>A		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7	c.483C>A	p.Tyr161Ter	stop_gained	6/14	5		ENSP00000303500
PAH	ENST00000551988.5	n.530+10855C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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 08, 2019

The c.498C>A (p.Tyr166Ter) variant in PAH is a nonsense variant in exon 5 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in individuals with Classic PKU in German and Chinese cohorts. (PP4, PMID:16256386; 10394930). This variant is absent from ExAC/gnomAD, 1000 Genomes, and ESP (PM2). This variant was detected with multiple known pathogenic variants (PM3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A
Vest4		0.88
GERP RS		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs199475645; hg19: chr12-103260385;