12-102839156-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received -3 ACMG points: 1P and 4B. PP4BS1

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

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:3B:5

Conservation

PhyloP100: -0.654

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 was made for transcript

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 link	c.*19G>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	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 link	c.*19G>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

194

AN:

152212

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00157

AC XY:

1140

AN XY:

724392

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

AC:

AN:

33356

Gnomad4 AMR exome

AF:

0.00177

AC:

AN:

44690

Gnomad4 ASJ exome

AF:

0.000728

AC:

AN:

26100

Gnomad4 EAS exome

AF:

0.00131

AC:

AN:

39666

Gnomad4 SAS exome

AF:

0.00822

AC:

708

AN:

86100

Gnomad4 FIN exome

AF:

0.0000750

AC:

AN:

53306

Gnomad4 NFE exome

AF:

0.000777

AC:

859

AN:

1106234

Gnomad4 Remaining exome

AF:

0.00153

AC:

AN:

60154

Heterozygous variant carriers

186

280

373

466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00127

AC:

194

AN:

152330

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000240

AC:

0.000240489

AN:

0.000240489

Gnomad4 AMR

AF:

0.00340

AC:

0.00339825

AN:

0.00339825

Gnomad4 ASJ

AF:

0.000577

AC:

0.000577034

AN:

0.000577034

Gnomad4 EAS

AF:

0.00154

AC:

0.00154202

AN:

0.00154202

Gnomad4 SAS

AF:

0.00786

AC:

0.00786424

AN:

0.00786424

Gnomad4 FIN

AF:

0.0000942

AC:

0.0000942329

AN:

0.0000942329

Gnomad4 NFE

AF:

0.00109

AC:

0.00108779

AN:

0.00108779

Gnomad4 OTH

AF:

0.00284

AC:

0.00283822

AN:

0.00283822

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.00114

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Uncertain:3Benign:1

May 18, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

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. -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

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

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