12-102866605-T-C

Position:

chr12-102866605-T-C

Variant summary

Our verdict is Uncertain significance. Variant got -3 ACMG points: 1P and 4B. PP4BS1

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PP4: N167S was observed in 1 case (genotype N167S/-) with benign persistent hyperphenylalaninemia (200-600 uM). (PMID:11385716); BS1: gnomAD MAF: 0.01461. 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: (PP4, BS1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229585/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.0042 ( 6 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 3 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:4O:1

Conservation

PhyloP100: 0.267

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 Uncertain_significance. Variant got -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/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.500A>G	p.Asn167Ser	missense_variant	5/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.500A>G	p.Asn167Ser	missense_variant	6/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.500A>G	p.Asn167Ser	missense_variant	5/7		XP_016874859.1
LOC124902999	XR_007063428.1 linkuse as main transcript	n.807+1378T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.500A>G	p.Asn167Ser	missense_variant	5/13	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000549111.5 linkuse as main transcript	n.596A>G		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7 linkuse as main transcript	c.485A>G	p.Asn162Ser	missense_variant	6/14	5		ENSP00000303500.2	J3KND8
PAH	ENST00000551988.5 linkuse as main transcript	n.530+10857A>G		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00415

AC:

631

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.0000294

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00104

AC:

261

AN:

251360

Hom.:

AF XY:

0.000751

AC XY:

102

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0147

Gnomad AMR exome

AF:

0.000550

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000399

AC:

583

AN:

1461170

Hom.:

Cov.:

AF XY:

0.000365

AC XY:

265

AN XY:

726938

show subpopulations

Gnomad4 AFR exome

AF:

0.0133

Gnomad4 AMR exome

AF:

0.000738

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.00416

AC:

633

AN:

152280

Hom.:

Cov.:

AF XY:

0.00387

AC XY:

288

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0146

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00150

Hom.:

Bravo

AF:

0.00464

ESP6500AA

AF:

0.0163

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00137

AC:

166

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:4Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Uncertain:2Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 11, 2020	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 13, 2018	PAH-specific ACMG/AMP criteria applied: PP4: N167S was observed in 1 case (genotype N167S/-) with benign persistent hyperphenylalaninemia (200-600 uM). (PMID:11385716); BS1: gnomAD MAF: 0.01461. 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: (PP4, BS1). -

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

0.071

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Pathogenic

0.95

D;D

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.87

D;D

MetaRNN

Benign

0.024

T;T

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

2.0

M;.

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.9

D;D

REVEL

Uncertain

0.38

Sift

Benign

0.17

T;T

Sift4G

Benign

0.26

T;T

Polyphen

0.0

B;.

Vest4

0.72

MVP

0.77

MPC

0.028

ClinPred

0.028

GERP RS

-4.0

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.25

gMVP

0.74

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