chr12-102843756-C-A

Position:

chr12-102843756-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 7 ACMG points: 8P and 1B. PM3_StrongPM2PP4_ModerateBP4

This summary comes from the ClinGen Evidence Repository: The c.1089G>T (p.Lys363Asn) variant in PAH has been reported in 3 patients with mild HPA and mild PKU. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out. It was detected in trans with pathogenic variants Phe55Leufs*6 (PMID:27121329) and c.442-1G>A (PMID:29316886). This variant is absent in population databases. However, multiple lines of computation evidence suggest no impact on the PAH protein. In summary, computational evidence conflicts with case level evidence and is therefore classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229334/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

Uncertain significance reviewed by expert panel U:2O:1

Conservation

PhyloP100: -0.107

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 made for transcript

Verdict is Uncertain_significance. 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.

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	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.1089G>T	p.Lys363Asn	missense_variant	11/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.1089G>T	p.Lys363Asn	missense_variant	12/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.1089G>T	p.Lys363Asn	missense_variant	11/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

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:

0.000193

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

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 25, 2017	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Feb 26, 2021	The c.1089G>T (p.Lys363Asn) variant in PAH has been reported in 3 patients with mild HPA and mild PKU. A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out. It was detected in trans with pathogenic variants Phe55Leufs*6 (PMID: 27121329) and c.442-1G>A (PMID: 29316886). This variant is absent in population databases. However, multiple lines of computation evidence suggest no impact on the PAH protein. In summary, computational evidence conflicts with case level evidence and is therefore classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, BP4. -

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

Benign

0.17

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Pathogenic

0.87

D;D

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.80

T;T

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

0.83

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.43

Sift

Benign

0.094

T;T

Sift4G

Benign

0.084

T;T

Polyphen

0.0

B;.

Vest4

0.74

MutPred

0.79

Loss of ubiquitination at K363 (P = 0.0141);.;

MVP

0.79

MPC

0.034

ClinPred

0.41

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.32

gMVP

0.84

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