rs5030847

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: gnomAD MAF: 0.00006; PP3: tools predict damaging ; PS3: 1% residual activity (PMID:25596310; PMID:17935162); PP4: Detection of codon 252arg>trp in a patient with PAH deficiency (PMID:2574153); PM3: Detected with IVS10-11G>A, R261Q, IVS12+1, R68S (all P/LP). (PMID:18299955; PMID:11524738). 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, PP4, PM3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA251529/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

16

2

Clinical Significance

Pathogenic reviewed by expert panel P:17O:1

Conservation

PhyloP100: 3.29

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), G2P, ClinGen, Myriad Women’s Health
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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.754C>T	p.Arg252Trp	missense	Exon 7 of 13	NP_000268.1
	PAH	NM_001354304.2		c.754C>T	p.Arg252Trp	missense	Exon 8 of 14	NP_001341233.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.754C>T	p.Arg252Trp	missense	Exon 7 of 13	ENSP00000448059.1
	PAH	ENST00000906695.1		c.754C>T	p.Arg252Trp	missense	Exon 7 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.754C>T	p.Arg252Trp	missense	Exon 7 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

8

AN:

152156

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000279

AC:

7

AN:

251272

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:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000417

AC:

61

AN:

1461832

Hom.:

0

Cov.:

31

AF XY:

0.0000454

AC XY:

33

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33478

American (AMR)

AF:

0.0000224

AC:

1

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26134

East Asian (EAS)

AF:

0.000151

AC:

6

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

1

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000441

AC:

49

AN:

1111976

Other (OTH)

AF:

0.0000662

AC:

4

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0

5

10

15

20

25

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:

0.0000526

AC:

8

AN:

152156

Hom.:

0

Cov.:

32

AF XY:

0.0000404

AC XY:

3

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41448

American (AMR)

AF:

0.00

AC:

0

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

8

AN:

68024

Other (OTH)

AF:

0.00

AC:

0

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.0000612

Hom.:

0

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000233

AC:

2

ExAC

AF:

0.0000494

AC:

6

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

11

-

-

Phenylketonuria (11)

4

-

-

not provided (5)

1

-

-

Pulmonary hypertension, primary, 1 (1)

1

-

-

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.43

D

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

27

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Uncertain

0.94

D

LIST_S2

Pathogenic

1.0

D

M_CAP

Pathogenic

0.78

D

MetaRNN

Pathogenic

0.98

D

MetaSVM

Pathogenic

0.93

D

MutationAssessor

Pathogenic

4.5

H

PhyloP100

3.3

PrimateAI

Pathogenic

0.85

D

PROVEAN

Pathogenic

-7.7

D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D

Sift4G

Uncertain

0.017

D

Polyphen

1.0

D

Vest4

0.97

MVP

0.99

MPC

0.24

ClinPred

1.0

D

GERP RS

3.9

PromoterAI

-0.050

Neutral

Varity_R

0.98

gMVP

0.96

Mutation Taster

=3/97

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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: rs5030847; hg19: chr12-103246681; COSMIC: COSV61019811; COSMIC: COSV61019811; API