rs1801152

Positions:

• chr12-102840473-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS2 BS1

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01361 in ENF from gnomAD; BS2: 19 homozygotes in gnomAD. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BS2). LINK:https://erepo.genome.network/evrepo/ui/classification/CA200893/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.0076 (4 hom., cov: 32)
  • Exomes 𝑓: 0.012 (139 hom.)
• Consequence: PAH NM_000277.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:13 O:1
• Conservation: PhyloP100: 1.43

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]

PAH (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.1242C>T	p.Tyr414Tyr	synonymous_variant	12/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1242C>T	p.Tyr414Tyr	synonymous_variant	13/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1242C>T	p.Tyr414Tyr	synonymous_variant	12/13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.00758 AC: 1153 AN: 152164 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00251

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0138

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00745 AC: 1874 AN: 251430 Hom.: 16 AF XY: 0.00730 AC XY: 992 AN XY: 135882

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.00701

GnomAD4 exome AF: 0.0120 AC: 17485 AN: 1461530 Hom.: 139 Cov.: 31 AF XY: 0.0115 AC XY: 8369 AN XY: 727108

Gnomad4 AFR exome AF: 0.00200

Gnomad4 AMR exome AF: 0.00376

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00179

Gnomad4 FIN exome AF: 0.00286

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.00762

GnomAD4 genome AF: 0.00757 AC: 1153 AN: 152282 Hom.: 4 Cov.: 32 AF XY: 0.00696 AC XY: 518 AN XY: 74452

Gnomad4 AFR AF: 0.00250

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.0138

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.0105 Hom.: 8

Bravo AF: 0.00779

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0134

EpiControl AF: 0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:13 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 29, 2018	Variant summary: PAH c.1242C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0074 in 277168 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.014 (in the gnomAD database), including 16 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.77 fold of the estimated maximal expected allele frequency for a pathogenic variant in PAH causing Hyperphenylalaninemia phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:4 Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2020	This variant is associated with the following publications: (PMID: 9781015) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	PAH: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 05, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Phenylketonuria Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 10, 2018	PAH-specific ACMG/AMP criteria applied: BS1: MAF=0.01361 in ENF from gnomAD; BS2: 19 homozygotes in gnomAD. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BS1, BS2). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.2
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1801152; hg19: chr12-103234251;