Genetic Variant PAH:c.168+19T>C (chr12-102912772-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: BA1: MAF=0.44942 in ExAC. 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: (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA145980/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.21 ( 3946 hom., cov: 32)

Exomes 𝑓: 0.17 ( 22653 hom. )

Consequence

PAH
NM_000277.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:12O:1

Conservation

PhyloP100: 2.01

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.168+19T>C	intron_variant	Intron 2 of 12	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.168+19T>C	intron_variant	Intron 3 of 13		NP_001341233.1
PAH	XM_017019370.2 link	c.168+19T>C	intron_variant	Intron 2 of 6		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.168+19T>C		intron_variant	Intron 2 of 12	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.210

AC:

31878

AN:

151974

Hom.:

3939

Cov.:

show subpopulations

Gnomad AFR

AF:

0.292

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.344

Gnomad ASJ

AF:

0.224

Gnomad EAS

AF:

0.0845

Gnomad SAS

AF:

0.202

Gnomad FIN

AF:

0.0872

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.160

Gnomad OTH

AF:

0.198

GnomAD3 exomes

AF:

0.202

AC:

50662

AN:

251168

Hom.:

6864

AF XY:

0.191

AC XY:

25860

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.296

Gnomad AMR exome

AF:

0.441

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.0824

Gnomad SAS exome

AF:

0.197

Gnomad FIN exome

AF:

0.0960

Gnomad NFE exome

AF:

0.155

Gnomad OTH exome

AF:

0.190

GnomAD4 exome

AF:

0.171

AC:

231573

AN:

1357404

Hom.:

22653

Cov.:

AF XY:

0.169

AC XY:

115544

AN XY:

681788

show subpopulations

Gnomad4 AFR exome

AF:

0.292

Gnomad4 AMR exome

AF:

0.428

Gnomad4 ASJ exome

AF:

0.215

Gnomad4 EAS exome

AF:

0.0926

Gnomad4 SAS exome

AF:

0.199

Gnomad4 FIN exome

AF:

0.0978

Gnomad4 NFE exome

AF:

0.159

Gnomad4 OTH exome

AF:

0.176

GnomAD4 genome

AF:

0.210

AC:

31892

AN:

152094

Hom.:

3946

Cov.:

AF XY:

0.209

AC XY:

15510

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.292

Gnomad4 AMR

AF:

0.344

Gnomad4 ASJ

AF:

0.224

Gnomad4 EAS

AF:

0.0841

Gnomad4 SAS

AF:

0.203

Gnomad4 FIN

AF:

0.0872

Gnomad4 NFE

AF:

0.160

Gnomad4 OTH

AF:

0.196

Alfa

AF:

0.176

Hom.:

2659

Bravo

AF:

0.230

Asia WGS

AF:

0.172

AC:

601

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Benign:7

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

PAH-specific ACMG/AMP criteria applied: BA1: MAF=0.44942 in ExAC; BP2: Observed in cis (in the homozygous state) with IVS2+5G>C (P) (PMID:24048906). 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: (BA1, BP2). -

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 16, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2Other:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23690520, 27884173, 32668217) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over