12-102894804-T-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3PP4PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.283A>T (p.Ile95Phe) variant in PAH has been reported in multiple patients with mild and moderate phenylketonuria. It was detected with pathogenic variants: p.R408W (PMID:10495930); p.R158Q, p.A403V, p.T323del (PMID:18299955); and p.E280K (PMID:31623983). This variant has a MAF of 0.00060 in gnomAD in the Ashkenazi Jewish population, which is above our cutoff for PM2 (<0.0002) and below our cutoff for BS1 (>0.002). Computational evidence support a deleterious effect (REVEL=0.658). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229507/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:6O:1

Conservation

PhyloP100: 2.73

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 Likely_pathogenic. Variant got 6 ACMG points.

PM3

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

PP3

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

PP4

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.283A>T	p.Ile95Phe	missense_variant	Exon 3 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.283A>T	p.Ile95Phe	missense_variant	Exon 4 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.283A>T	p.Ile95Phe	missense_variant	Exon 3 of 7		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.863-9894T>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.283A>T	p.Ile95Phe	missense_variant	Exon 3 of 13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

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:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251440

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000595

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:

0.00000684

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000344

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:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:5

Sep 21, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 95 of the PAH protein (p.Ile95Phe). This variant is present in population databases (rs62508682, gnomAD 0.05%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 10495930, 18299955, 32668217; BIOPKU http://www.biopku.org). ClinVar contains an entry for this variant (Variation ID: 102645). 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 with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Mar 02, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PAH c.283A>T (p.Ile95Phe) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251440 control chromosomes (gnomAD). c.283A>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Bercovich_2008, Zekanowski_1999, Rajabi_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18299955, 10495930, 29144512, 31623983). ClinVar contains an entry for this variant (Variation ID: 102645). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 06, 2024

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.283A>T (p.Ile95Phe) variant in PAH has been reported in multiple patients with mild and moderate phenylketonuria. It was detected with pathogenic variants: p.R408W (PMID: 10495930); p.R158Q, p.A403V, p.T323del (PMID: 18299955); and p.E280K (PMID: 31623983). This variant has a MAF of 0.00060 in gnomAD in the Ashkenazi Jewish population, which is above our cutoff for PM2 (<0.0002) and below our cutoff for BS1 (>0.002). Computational evidence support a deleterious effect (REVEL=0.658). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP3, PP4. -

not provided

Pathogenic:1Other:1

May 14, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 10495930, 29144512, 18299955, 11096279, 32668217, 18294361, 11678552, 31623983) -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.86

D;D;T;T

Eigen

Benign

-0.065

Eigen_PC

Benign

0.084

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.79

T;T;T;T

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.6

L;.;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Pathogenic

0.66

Sift

Benign

0.16

T;T;D;D

Sift4G

Benign

0.25

T;T;T;.

Polyphen

0.081

B;.;.;.

Vest4

0.58

MutPred

0.82

Gain of methylation at K96 (P = 0.0379);.;Gain of methylation at K96 (P = 0.0379);Gain of methylation at K96 (P = 0.0379);

MVP

0.94

MPC

0.044

ClinPred

0.53

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.82

gMVP

0.87

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