Genetic Variant NM_000277.3:c.1242C>T (chr12-102840473-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS2BS1

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

Scores

Clinical Significance

Benign reviewed by expert panel B:13O:1

Conservation

PhyloP100: 1.43

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.

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 rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.1242C>T	p.Tyr414Tyr	synonymous_variant	Exon 12 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.1242C>T	p.Tyr414Tyr	synonymous_variant	Exon 13 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.1242C>T	p.Tyr414Tyr	synonymous_variant	Exon 12 of 13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.00758

AC:

1153

AN:

152164

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00730

AC XY:

992

AN XY:

135882

show subpopulations

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.:

AF XY:

0.0115

AC XY:

8369

AN XY:

727108

show subpopulations

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.:

Cov.:

AF XY:

0.00696

AC XY:

518

AN XY:

74452

show subpopulations

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.:

Bravo

AF:

0.00779

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0134

EpiControl

AF:

0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:13Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 29, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 18, 2015

Eurofins Ntd Llc (ga)

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:4Other:1

Apr 05, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PAH: BP4, BP7, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 9781015) -

Phenylketonuria

Benign:4

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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: 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). -

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

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