12-102840463-T-G

Position:

chr12-102840463-T-G

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PP3PM3PM2PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1252A>C (p.Thr418Pro) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded). (PMID:26503515). This variant has an extremely low allele frequency (MAF=0.00003) in gnomAD. It was detected in trans with multiple pathogenic variants: p.Arg243Gln, p.Arg408Gln, p.Arg176*, EX6-96A＞G, p.Tyr356*, p.Arg111* (PMID:28982351). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229418/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:4O:1

Conservation

PhyloP100: 5.85

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:

PAH (HGNC:):

PAH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 7 ACMG points.

PM2

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

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/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.1252A>C	p.Thr418Pro	missense_variant	12/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.1252A>C	p.Thr418Pro	missense_variant	13/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.1252A>C	p.Thr418Pro	missense_variant	12/13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00000398

AC:

AN:

251448

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461750

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 06, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 19, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 418 of the PAH protein (p.Thr418Pro). This variant is present in population databases (rs62644501, gnomAD 0.003%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 1301187, 26322415, 29499199, 29731766, 30747360, 31355225). ClinVar contains an entry for this variant (Variation ID: 102580). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jun 08, 2020	The c.1252A>C (p.Thr418Pro) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded). (PMID: 26503515). This variant has an extremely low allele frequency (MAF=0.00003) in gnomAD. It was detected in trans with multiple pathogenic variants: p.Arg243Gln, p.Arg408Gln, p.Arg176, EX6-96Aï¼žG, p.Tyr356, p.Arg111* (PMID: 28982351). Computational prediction tools and conservation analysis support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4_Moderate, PP3. -

not provided

Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.57

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

H;.

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.98

Gain of catalytic residue at T418 (P = 0.0535);.;

MVP

0.99

MPC

0.24

ClinPred

1.0

GERP RS

4.2

Varity_R

0.97

gMVP

0.95

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