12-102852902-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3PM3PS3PP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: ; PP3: tools predict damaging; PS3: BioPKU 3% enzyme activity; 3.8% residual activity (PMID:24401910); PM3: Detected in trans with p.Pro407fs (PMID:7833954); PP4_Moderate: Detected in 2 patients with classic PKU (Phe>1.5mM). BH4 deficiency excluded (PMID:7833954; PMID:9634518). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PS3, PM3, PP4_Moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229743/MONDO:0009861/006

Frequency

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

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

15

3

Clinical Significance

Pathogenic reviewed by expert panel P:12O:1

Conservation

PhyloP100: 7.91

Publications

33 publications found

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 Gene-Disease associations (from GenCC):

phenylketonuria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
classic phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
maternal phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild hyperphenylalaninemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PAH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS3

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

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.755G>A	p.Arg252Gln	missense	Exon 7 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.755G>A	p.Arg252Gln	missense	Exon 8 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.755G>A	p.Arg252Gln	missense	Exon 7 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.755G>A	p.Arg252Gln	missense	Exon 7 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.755G>A	p.Arg252Gln	missense	Exon 7 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

2

AN:

152030

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

2

AN:

251262

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

9

AN:

1461852

Hom.:

0

Cov.:

31

AF XY:

0.00000688

AC XY:

5

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.0000299

AC:

1

AN:

33478

American (AMR)

AF:

0.00

AC:

0

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

2

AN:

39696

South Asian (SAS)

AF:

0.0000348

AC:

3

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

3

AN:

1111988

Other (OTH)

AF:

0.00

AC:

0

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0

1

2

3

4

5

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

2

4

6

8

10

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

2

AN:

152030

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.0000242

AC:

1

AN:

41370

American (AMR)

AF:

0.00

AC:

0

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

1

AN:

68012

Other (OTH)

AF:

0.00

AC:

0

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.650

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000106

Hom.:

0

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

9

-

-

Phenylketonuria (9)

3

-

-

not provided (4)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.45

D

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

33

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

D

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Pathogenic

1.0

D

M_CAP

Pathogenic

0.45

D

MetaRNN

Pathogenic

0.99

D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

3.1

M

PhyloP100

7.9

PrimateAI

Uncertain

0.77

T

PROVEAN

Uncertain

-3.8

D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D

Sift4G

Uncertain

0.0020

D

Polyphen

1.0

D

Vest4

0.85

MutPred

0.96

Loss of methylation at R252 (P = 0.0335)

MVP

0.99

MPC

0.25

ClinPred

1.0

D

GERP RS

5.9

PromoterAI

-0.030

Neutral

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.94

Mutation Taster

=5/95

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs62644503; hg19: chr12-103246680; API