12-102843683-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4PP3PM3PS3PM2

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: Extremely low in ExAC and 1000 genomes (PMID:9860305); PS3: PAH activity in COS cell expression system 15% (PMID:9860305); PM3: Compound het with severe mutation (PMID:9860305); PP3: ; PP4: Reported in patient with classic PKU (PMID:9860305). 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, PS3, PM3, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA251543/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

10

6

2

Clinical Significance

Pathogenic reviewed by expert panel P:14O:1

Conservation

PhyloP100: 5.04

Publications

59 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 10 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.1162G>A	p.Val388Met	missense	Exon 11 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.1162G>A	p.Val388Met	missense	Exon 12 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.1162G>A	p.Val388Met	missense	Exon 11 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.1261G>A	p.Val421Met	missense	Exon 12 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.1240G>A	p.Val414Met	missense	Exon 11 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

7

AN:

151940

Hom.:

0

Cov.:

31

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.0000836

AC:

21

AN:

251286

AF XY:

0.0000810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000363

AC:

53

AN:

1461564

Hom.:

0

Cov.:

30

AF XY:

0.0000344

AC XY:

25

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33466

American (AMR)

AF:

0.000559

AC:

25

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26132

East Asian (EAS)

AF:

0.0000756

AC:

3

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

2

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000189

AC:

21

AN:

1111772

Other (OTH)

AF:

0.0000331

AC:

2

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0

4

8

12

16

20

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:

0.0000461

AC:

7

AN:

151940

Hom.:

0

Cov.:

31

AF XY:

0.0000539

AC XY:

4

AN XY:

74208

show subpopulations

African (AFR)

AF:

0.0000726

AC:

3

AN:

41350

American (AMR)

AF:

0.000196

AC:

3

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4794

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

0

AN:

67992

Other (OTH)

AF:

0.000480

AC:

1

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.0000551

Hom.:

0

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000227

AC:

1

ESP6500EA

AF:

0.00

AC:

0

ExAC

AF:

0.0000659

AC:

8

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

12

-

-

Phenylketonuria (12)

2

-

-

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.30

D

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

25

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Pathogenic

0.99

D

M_CAP

Pathogenic

0.77

D

MetaRNN

Pathogenic

0.94

D

MetaSVM

Pathogenic

0.98

D

MutationAssessor

Pathogenic

3.7

H

PhyloP100

5.0

PrimateAI

Uncertain

0.69

T

PROVEAN

Benign

-1.9

N

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0070

D

Sift4G

Uncertain

0.0080

D

Polyphen

1.0

D

Vest4

0.93

MVP

0.99

MPC

0.24

ClinPred

0.81

D

GERP RS

5.3

Varity_R

0.76

gMVP

0.94

Mutation Taster

=8/92

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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: rs62516101; hg19: chr12-103237461; COSMIC: COSV61017905; API