rs62642935

Variant names:

Your query was ambiguous. Multiple possible variants found:

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: Low frequency. 1.0e-5; PP3: All databases agree on damaging effect. REVEL=0.921; PS3: Enzyme activity = 30% (Ho, 2008) (PMID:18590700); PM3: Single patient with classic PKU, c.842C>T (pathogenic in ClinVar) / c.926C>T (PMID:26666653); PP4: Single patient with classic PKU (>1200umol/L), BH4 defect not excluded (PMID:26666653). 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA220592/MONDO:0009861/006

Frequency

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

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

11

7

Clinical Significance

Pathogenic reviewed by expert panel P:9O:1

Conservation

PhyloP100: 9.60

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 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.926C>T	p.Ala309Val	missense	Exon 9 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.926C>T	p.Ala309Val	missense	Exon 10 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.926C>T	p.Ala309Val	missense	Exon 9 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.1025C>T	p.Ala342Val	missense	Exon 10 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.926C>T	p.Ala309Val	missense	Exon 9 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

2

AN:

152080

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

4

AN:

251284

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000240

AC:

35

AN:

1461352

Hom.:

0

Cov.:

30

AF XY:

0.0000261

AC XY:

19

AN XY:

727014

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33446

American (AMR)

AF:

0.00

AC:

0

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39694

South Asian (SAS)

AF:

0.0000232

AC:

2

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000297

AC:

33

AN:

1111580

Other (OTH)

AF:

0.00

AC:

0

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

0

3

5

8

10

13

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:

152080

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41396

American (AMR)

AF:

0.00

AC:

0

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

2

AN:

68018

Other (OTH)

AF:

0.00

AC:

0

AN:

2090

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:

0.0000262

Hom.:

0

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000116

AC:

1

ExAC

AF:

0.00000824

AC:

1

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

6

-

-

Phenylketonuria (6)

2

-

-

not provided (3)

1

-

-

PAH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.47

D

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

30

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

1.0

D

LIST_S2

Pathogenic

0.98

D

M_CAP

Pathogenic

0.75

D

MetaRNN

Pathogenic

0.96

D

MetaSVM

Pathogenic

0.99

D

MutationAssessor

Uncertain

2.9

M

PhyloP100

9.6

PrimateAI

Uncertain

0.67

T

PROVEAN

Uncertain

-3.4

D

REVEL

Pathogenic

0.92

Sift

Uncertain

0.015

D

Sift4G

Uncertain

0.021

D

Polyphen

1.0

D

Vest4

0.96

MVP

0.98

MPC

0.20

ClinPred

0.94

D

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.95

Mutation Taster

=0/100

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.050

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: rs62642935; hg19: chr12-103240716; COSMIC: COSV100187930; API