12-102852828-A-C

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: The c.829T>G (p.Tyr277Asp) variant in PAH has been reported in 2 individuals with Classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID:8268925; PMID:23500595). This variant has an extremely low allele frequency (1/121400) in ExAC (PM2; http://exac.broadinstitute.org). This variant has 0% enzyme activity (PS3; http://www.biopku.org/centralStore/biopku/PAH%20activity.pdf). This variant was detected in trans with L48S (Pathogenic in ClinVar) (PM3; PMID:23500595). Computational prediction tools and conservation analysis suggest that the c.829T>G variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA251534/MONDO:0009861/006

Frequency

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

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

14

4

Clinical Significance

Pathogenic reviewed by expert panel P:13O:1

Conservation

PhyloP100: 7.52

Publications

19 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.829T>G	p.Tyr277Asp	missense	Exon 7 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.829T>G	p.Tyr277Asp	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.829T>G	p.Tyr277Asp	missense	Exon 7 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.829T>G	p.Tyr277Asp	missense	Exon 7 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.829T>G	p.Tyr277Asp	missense	Exon 7 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152188

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000159

AC:

4

AN:

251352

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000376

AC:

55

AN:

1461776

Hom.:

0

Cov.:

31

AF XY:

0.0000344

AC XY:

25

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.0000299

AC:

1

AN:

33470

American (AMR)

AF:

0.0000224

AC:

1

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000459

AC:

51

AN:

1111938

Other (OTH)

AF:

0.0000331

AC:

2

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0

3

6

9

12

15

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

4

8

12

16

20

<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:

0.0000131

AC:

2

AN:

152188

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0000241

AC:

1

AN:

41448

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:

5196

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

1

AN:

68030

Other (OTH)

AF:

0.00

AC:

0

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0

1

1

2

2

3

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000321

Hom.:

0

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

1

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

9

-

-

Phenylketonuria (9)

3

-

-

not provided (4)

1

-

-

PAH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.50

D

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

27

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

1.0

D

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Uncertain

0.94

D

M_CAP

Pathogenic

0.73

D

MetaRNN

Pathogenic

0.98

D

MetaSVM

Pathogenic

0.95

D

MutationAssessor

Pathogenic

4.8

H

PhyloP100

7.5

PrimateAI

Pathogenic

0.85

D

PROVEAN

Pathogenic

-9.6

D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0050

D

Sift4G

Uncertain

0.015

D

Polyphen

1.0

D

Vest4

0.96

MVP

0.99

MPC

0.29

ClinPred

1.0

D

GERP RS

4.6

PromoterAI

0.037

Neutral

Varity_R

0.94

gMVP

0.99

Mutation Taster

=1/99

disease causing (ClinVar)

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

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Other links and lift over

dbSNP: rs78655458; hg19: chr12-103246606; API