chr12-102839156-C-A

Variant names:

• chr12-102839156-C-A
• rs372637021
• NM_000277.3:c.*19G>T

Variant summary

Our verdict is Uncertain significance. The variant received -3 ACMG points: 1P and 4B. PP4 BS1

This summary comes from the ClinGen Evidence Repository: The c.*19G>T variant in PAH has been reported in a 2 patients with PKU (PP4; PMID:12765842, 26210745) This variant has an allele frequency greater than expected: gnomAD MAF=0.00812 (>0.002) and 8 homozygotes (BS1). Computational evidence is conflicting (TraP score: 0.085; HSF: activation of an exonic cryptic donor site; MaxENT 3' Motif:+1145.71). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, BS1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748669/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (14 hom.)
• Consequence: PAH NM_000277.3 3_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:3 B:5
• Conservation: PhyloP100: -0.654
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received -3 ACMG points.

• PP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: 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	c.*19G>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.*19G>T		3_prime_UTR_variant	Exon 14 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.*19G>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 194 AN: 152212 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00786

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00219 AC: 550 AN: 250934 AF XY: 0.00271

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00250

Gnomad FIN exome AF: 0.0000926

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00129 AC: 1882 AN: 1455368 Hom.: 14 Cov.: 29 AF XY: 0.00157 AC XY: 1140 AN XY: 724392

African (AFR) AF: 0.0000300 AC: 1 AN: 33356

American (AMR) AF: 0.00177 AC: 79 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000728 AC: 19 AN: 26100

East Asian (EAS) AF: 0.00131 AC: 52 AN: 39666

South Asian (SAS) AF: 0.00822 AC: 708 AN: 86100

European-Finnish (FIN) AF: 0.0000750 AC: 4 AN: 53306

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5762

European-Non Finnish (NFE) AF: 0.000777 AC: 859 AN: 1106234

Other (OTH) AF: 0.00153 AC: 92 AN: 60154

GnomAD4 genome AF: 0.00127 AC: 194 AN: 152330 Hom.: 1 Cov.: 33 AF XY: 0.00144 AC XY: 107 AN XY: 74488

African (AFR) AF: 0.000240 AC: 10 AN: 41582

American (AMR) AF: 0.00340 AC: 52 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5188

South Asian (SAS) AF: 0.00786 AC: 38 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.00114

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Uncertain:3 Benign:1

Apr 27, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 18, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 27, 2019

ClinGen PAH Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.*19G>T variant in PAH has been reported in a 2 patients with PKU (PP4; PMID: 12765842, 26210745) This variant has an allele frequency greater than expected: gnomAD MAF=0.00812 (>0.002) and 8 homozygotes (BS1). Computational evidence is conflicting (TraP score: 0.085; HSF: activation of an exonic cryptic donor site; MaxENT 3' Motif:+1145.71). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, BS1. -

not specified Benign:4

Aug 17, 2017

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAH c.*19G>T is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.0022 in 252634 control chromosomes (gnomAD, da Silva_2003, Alibakhshi_2022), predominantly at a frequency of 0.0081 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. This frequency is slightly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.0081 vs 0.0079), suggesting this variant is likely a benign polymorphism found primarily in South Asians. The variant has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (da Silva_2003, Trunzo_2015). However, co-occurrence with another pathogenic variant (in cis) has been reported (PAH c.1223G>A, p.R408Q), providing supporting evidence for a benign role (Trunzo_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed the variant since 2014: three submitters (including one expert panel) classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.63
PhyloP100		-0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs372637021; hg19: chr12-103232934; COSMIC: COSV107395860; COSMIC: COSV107395860;