chr12-102912772-A-G

Position:

• chr12-102912772-A-G

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
• Clinical Significance: Benign reviewed by expert panel B:12 O:1
• Conservation: PhyloP100: 2.01

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.

• BA1: 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.168+19T>C		intron_variant		ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.168+19T>C		intron_variant			NP_001341233.1
PAH	XM_017019370.2	c.168+19T>C		intron_variant			XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.168+19T>C		intron_variant		1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31878 AN: 151974 Hom.: 3939 Cov.: 32

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

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.: 21 AF XY: 0.169 AC XY: 115544 AN XY: 681788

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.: 32 AF XY: 0.209 AC XY: 15510 AN XY: 74378

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:12 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Benign:7

Benign, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 10, 2018	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). -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 30, 2019	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 16, 2017	- -

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 23690520, 27884173, 32668217) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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_noAF	Benign	-0.80
CADD	Benign	13
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

Other links and lift over

dbSNP: rs17842947; hg19: chr12-103306550; COSMIC: COSV61016895; COSMIC: COSV61016895;