12-102866612-C-T

Position:

chr12-102866612-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM3PP1PP3PP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: The c.493G>A (p.Ala165Thr) variant in PAH has been reported in multiple individuals with PKU, including siblings (BH4 deficiency excluded). (PP4_Moderate, PMID:8981952; PP1, PMID:26666653). This variant has extremely low frequency in gnomAD (MAF=0.00001) (PM2). This variant was detected with c.1066-11G>A (PM3; PMID:10598814). Multiple lines of computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229579/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

13

5

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:2O:1

Conservation

PhyloP100: 5.24

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:

PAH (HGNC:):

PAH links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 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.

PP1

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.493G>A	p.Ala165Thr	missense_variant	5/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.493G>A	p.Ala165Thr	missense_variant	6/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.493G>A	p.Ala165Thr	missense_variant	5/7		XP_016874859.1
LOC124902999	XR_007063428.1 linkuse as main transcript	n.807+1385C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.493G>A	p.Ala165Thr	missense_variant	5/13	1	NM_000277.3	ENSP00000448059.1		P00439
PAH	ENST00000549111.5 linkuse as main transcript	n.589G>A		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7 linkuse as main transcript	c.478G>A	p.Ala160Thr	missense_variant	6/14	5		ENSP00000303500.2		J3KND8
PAH	ENST00000551988.5 linkuse as main transcript	n.530+10850G>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152126

Hom.:

0

Cov.:

32

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

1

AN:

251346

Hom.:

0

AF XY:

0.00000736

AC XY:

1

AN XY:

135838

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

4

AN:

1461362

Hom.:

0

Cov.:

30

AF XY:

0.00000413

AC XY:

3

AN XY:

727010

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

2

AN:

152126

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74310

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Apr 07, 2019	The c.493G>A (p.Ala165Thr) variant in PAH has been reported in multiple individuals with PKU, including siblings (BH4 deficiency excluded). (PP4_Moderate, PMID: 8981952; PP1, PMID: 26666653). This variant has extremely low frequency in gnomAD (MAF=0.00001) (PM2). This variant was detected with c.1066-11G>A (PM3; PMID: 10598814). Multiple lines of computational evidence support a deleterious effect (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3, PP1, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2021	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 102700). This missense change has been observed in individual(s) with phenylketonuria (PMID: 26666653). This variant is present in population databases (rs199475626, gnomAD 0.0009%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 165 of the PAH protein (p.Ala165Thr). -

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

0.87

BayesDel_addAF

Pathogenic

0.53

D

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

29

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.78

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.96

D

MutationAssessor

Pathogenic

4.1

H;.

PrimateAI

Uncertain

0.68

T

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.0080

D;D

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.97

Loss of stability (P = 0.0687);.;

MVP

0.99

MPC

0.23

ClinPred

0.99

D

GERP RS

6.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.0

Varity_R

0.64

gMVP

0.96

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.

Other links and lift over

dbSNP: rs199475626; hg19: chr12-103260390;