12-102894798-T-G

Position:

chr12-102894798-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP4BP4

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: BP4: Tolerated in SIFT, benign in Polyphen-2, Polymorphism in MutationTaster. REVEL=0.511; PP4: Seen in patient with mild HPA (PMID:17627389). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BP4, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748987/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:6

Conservation

PhyloP100: 1.24

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:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PAH	NM_000277.3 linkuse as main transcript	c.289A>C	p.Ile97Leu	missense_variant	3/13	ENST00000553106.6	NP_000268.1
LOC124902999	XR_007063428.1 linkuse as main transcript	n.863-9900T>G		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2 linkuse as main transcript	c.289A>C	p.Ile97Leu	missense_variant	4/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.289A>C	p.Ile97Leu	missense_variant	3/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.289A>C	p.Ile97Leu	missense_variant	3/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251446

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00215

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000458

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00158

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000525

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00176

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.000559

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 20, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 97 of the PAH protein (p.Ile97Leu). This variant is present in population databases (rs142516271, gnomAD 0.2%). This missense change has been observed in individual(s) with mild hyperphenylalaninemia (PMID: 17627389). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 376937). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 07, 2018	PAH-specific ACMG/AMP criteria applied: BP4: Tolerated in SIFT, benign in Polyphen-2, Polymorphism in MutationTaster. REVEL=0.511; PP4: Seen in patient with mild HPA (PMID:17627389). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BP4, PP4). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 25, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 07, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 12, 2024

Variant summary: PAH c.289A>C (p.Ile97Leu) results in a conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251446 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00016 vs 0.0079), allowing no conclusion about variant significance. c.289A>C has been reported in the literature in individuals affected with persistent hyperphenylalaninemia. These report(s) do not provide unequivocal conclusions about association of the variant with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30311390, 17627389). ClinVar contains an entry for this variant (Variation ID: 376937). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Apr 25, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.60

D;T;T;T

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.76

T;T;T;T

M_CAP

Uncertain

0.094

MetaRNN

Benign

0.018

T;T;T;T

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

0.42

N;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

0.22

N;N;N;N

REVEL

Uncertain

0.51

Sift

Benign

0.34

T;T;T;T

Sift4G

Benign

0.36

T;T;T;.

Polyphen

0.0020

B;.;.;.

Vest4

0.76

MVP

0.83

MPC

0.031

ClinPred

0.030

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.59

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