12-102852935-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3PM5PM3_StrongPP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC, gnomAD, 1000G, ESP (0.000077- 0.0001518); PP3: Predicted deleterious in SIFT, PolyPhen2, MutationTaster; PM5: R241C (VarID 102803) is Pathogenic in ClinVar based on 3 submitters; PP4_Moderate: R241H seen in 1 PKU patient. BH4 deficiency ruled out. Upgraded per ClinGen Metabolism WG. (PMID:8268925); PM3_Strong: R241H detected in trans with pathogenic variants (IVS10, R408W, R252W). Upgraded per ClinGen SVI Workgroup. (PMID:9429153). 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, PM5, PP4_Moderate, PM3_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA286507/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

10

5

3

Clinical Significance

Pathogenic reviewed by expert panel P:17O:1

Conservation

PhyloP100: 4.91

Publications

32 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.

PM2

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

PM3

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

PM5

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.722G>A	p.Arg241His	missense	Exon 7 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.722G>A	p.Arg241His	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.722G>A	p.Arg241His	missense	Exon 7 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.722G>A	p.Arg241His	missense	Exon 7 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.722G>A	p.Arg241His	missense	Exon 7 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

7

AN:

152008

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000167

AC:

42

AN:

251030

AF XY:

0.000133

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.0000992

AC:

145

AN:

1461832

Hom.:

0

Cov.:

32

AF XY:

0.0000921

AC XY:

67

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33480

American (AMR)

AF:

0.00

AC:

0

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00268

AC:

70

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

1

AN:

39694

South Asian (SAS)

AF:

0.0000812

AC:

7

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

1

AN:

53406

Middle Eastern (MID)

AF:

0.000173

AC:

1

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000405

AC:

45

AN:

1111978

Other (OTH)

AF:

0.000331

AC:

20

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0

10

21

31

42

52

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:

0.0000461

AC:

7

AN:

152008

Hom.:

0

Cov.:

32

AF XY:

0.0000539

AC XY:

4

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.0000242

AC:

1

AN:

41370

American (AMR)

AF:

0.00

AC:

0

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

4

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5170

South Asian (SAS)

AF:

0.000208

AC:

1

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

1

AN:

68020

Other (OTH)

AF:

0.00

AC:

0

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

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:

0.000122

Hom.:

0

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000116

AC:

1

ExAC

AF:

0.0000988

AC:

12

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

13

-

-

Phenylketonuria (13)

3

-

-

not provided (4)

1

-

-

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Pathogenic

0.36

D

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

32

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.95

D

LIST_S2

Uncertain

0.97

D

M_CAP

Pathogenic

0.74

D

MetaRNN

Uncertain

0.65

D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

3.1

M

PhyloP100

4.9

PrimateAI

Pathogenic

0.84

D

PROVEAN

Benign

-2.0

N

REVEL

Pathogenic

0.89

Sift

Uncertain

0.027

D

Sift4G

Benign

0.13

T

Polyphen

1.0

D

Vest4

0.74

MVP

0.97

MPC

0.25

ClinPred

0.44

T

GERP RS

5.0

PromoterAI

-0.096

Neutral

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.74

gMVP

0.89

Mutation Taster

=15/85

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs62508730; hg19: chr12-103246713; COSMIC: COSV100187953; COSMIC: COSV100187953; API