12-102852936-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP3PS3PM3_StrongPM2PP4_Moderate

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC (0.00014) and gnomAD (0.0001301); PP3: Deleterious effect predicted in SIFT, PolyPhen2, MutationTaster; PP4_Moderate: Seen in multiple PKU patients. BH4 deficiency excluded in 2 patients. Upgraded per ClinGen Metabolic Workgroup. (PMID:8222245; PMID:11142755); PM3_Strong: R241C seen once in trans with R413P, and once with R243Q, both pathogenic. Upgraded per ClinGen SVI Workgroup. (PMID:11142755); PS3: In vitro PAH R241C mutant was found to have 25% PAH activity of normal. In vivo phenylalanine breath test measured a decreased level in R241C homozygote. (PMID:15319459; PMID:7915167). 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, PP4_Moderate, PM3_Strong, PS3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA273357/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

10

5

3

Clinical Significance

Pathogenic reviewed by expert panel P:20O:1

Conservation

PhyloP100: 6.65

Publications

90 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 13 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.721C>T	p.Arg241Cys	missense	Exon 7 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.721C>T	p.Arg241Cys	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.721C>T	p.Arg241Cys	missense	Exon 7 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.721C>T	p.Arg241Cys	missense	Exon 7 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.721C>T	p.Arg241Cys	missense	Exon 7 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

14

AN:

152082

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000774

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000143

AC:

36

AN:

250956

AF XY:

0.000147

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00142

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

65

AN:

1461820

Hom.:

0

Cov.:

32

AF XY:

0.0000440

AC XY:

32

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.000119

AC:

4

AN:

33480

American (AMR)

AF:

0.00

AC:

0

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26136

East Asian (EAS)

AF:

0.000680

AC:

27

AN:

39694

South Asian (SAS)

AF:

0.0000580

AC:

5

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000216

AC:

24

AN:

1111978

Other (OTH)

AF:

0.0000828

AC:

5

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0

4

9

13

18

22

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:

0.0000920

AC:

14

AN:

152200

Hom.:

0

Cov.:

32

AF XY:

0.0000941

AC XY:

7

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.000120

AC:

5

AN:

41548

American (AMR)

AF:

0.00

AC:

0

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3470

East Asian (EAS)

AF:

0.000776

AC:

4

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

4

AN:

68016

Other (OTH)

AF:

0.000475

AC:

1

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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

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:

0.0000497

Hom.:

0

Bravo

AF:

0.000147

ExAC

AF:

0.000140

AC:

17

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

13

-

-

Phenylketonuria (13)

6

-

-

not provided (7)

1

-

-

PAH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.20

D

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

33

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Benign

0.78

T

M_CAP

Pathogenic

0.37

D

MetaRNN

Uncertain

0.70

D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.2

M

PhyloP100

6.6

PrimateAI

Pathogenic

0.87

D

PROVEAN

Uncertain

-2.5

D

REVEL

Pathogenic

0.86

Sift

Benign

0.043

D

Sift4G

Uncertain

0.048

D

Polyphen

1.0

D

Vest4

0.91

MVP

0.97

MPC

0.086

ClinPred

0.12

T

GERP RS

5.9

PromoterAI

-0.10

Neutral

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.93

Mutation Taster

=17/83

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: rs76687508; hg19: chr12-103246714; COSMIC: COSV61018094; COSMIC: COSV61018094; API