12-102839156-C-A

Position:

• chr12-102839156-C-A

Variant summary

Our verdict is Uncertain significance. Variant got -3 ACMG points: 1P and 4B. BS1 PP4

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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got -3 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.*19G>T		3_prime_UTR_variant	13/13	ENST00000553106.6
PAH	NM_001354304.2	c.*19G>T		3_prime_UTR_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.*19G>T		3_prime_UTR_variant	13/13	1	NM_000277.3	P1
PAH	ENST00000307000.7	c.*19G>T		3_prime_UTR_variant	14/14	5
PAH	ENST00000551114.2	n.1040G>T		non_coding_transcript_exon_variant	6/6	2
PAH	ENST00000635528.1	n.893G>T		non_coding_transcript_exon_variant	5/5	3

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

GnomAD3 exomes AF: 0.00219 AC: 550 AN: 250934 Hom.: 8 AF XY: 0.00271 AC XY: 367 AN XY: 135640

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 SAS exome AF: 0.00810

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

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.000728

Gnomad4 EAS exome AF: 0.00131

Gnomad4 SAS exome AF: 0.00822

Gnomad4 FIN exome AF: 0.0000750

Gnomad4 NFE exome AF: 0.000777

Gnomad4 OTH exome AF: 0.00153

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

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00786

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00284

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

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Sep 27, 2019	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2023	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 17, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2023	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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2017	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.63
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: rs372637021; hg19: chr12-103232934;