rs539743701

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3PM3PM5PP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: This c.463C>T (p.Arg155Cys) variant in PAH was reported in at least one patient with mild HPA detected in trans with pathogenic variant p.Gly289Arg (PMID:27121329). A defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels as well as by measuring the dihydropteridine reductase activity. Computational evidence supports a deleterious effect. This variant is observed at an amino acid residue where two other pathogenic missense variants have also been observed. This variant is seen at an extremely low frequency in population databases. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM5, PM3, PM2, PP4_moderate, and PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6748917/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

15

3

Clinical Significance

Likely pathogenic reviewed by expert panel P:6U:1

Conservation

PhyloP100: 2.87

Publications

1 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), 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:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 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.463C>T	p.Arg155Cys	missense	Exon 5 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.463C>T	p.Arg155Cys	missense	Exon 6 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.463C>T	p.Arg155Cys	missense	Exon 5 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.559C>T		non_coding_transcript_exon	Exon 5 of 6
	PAH	ENST00000906695.1		c.463C>T	p.Arg155Cys	missense	Exon 5 of 14	ENSP00000576754.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

1

AN:

152088

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

5

AN:

251344

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

19

AN:

1461364

Hom.:

0

Cov.:

31

AF XY:

0.0000124

AC XY:

9

AN XY:

727010

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33456

American (AMR)

AF:

0.0000447

AC:

2

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39696

South Asian (SAS)

AF:

0.0000928

AC:

8

AN:

86246

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:

0.00000810

AC:

9

AN:

1111596

Other (OTH)

AF:

0.00

AC:

0

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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

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:

0.00000657

AC:

1

AN:

152206

Hom.:

0

Cov.:

32

AF XY:

0.0000134

AC XY:

1

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41520

American (AMR)

AF:

0.00

AC:

0

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

1

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

0

AN:

68016

Other (OTH)

AF:

0.00

AC:

0

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

0

Bravo

AF:

0.00000756

ExAC

AF:

0.0000330

AC:

4

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

6

1

-

Phenylketonuria (7)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.42

D

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

27

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.90

D

LIST_S2

Pathogenic

0.99

D

M_CAP

Pathogenic

0.79

D

MetaRNN

Pathogenic

0.99

D

MetaSVM

Pathogenic

0.95

D

MutationAssessor

Pathogenic

4.0

H

PhyloP100

2.9

PrimateAI

Uncertain

0.74

T

PROVEAN

Pathogenic

-7.4

D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D

Sift4G

Pathogenic

0.0

D

Polyphen

1.0

D

Vest4

0.95

MutPred

0.89

Loss of MoRF binding (P = 0.0021)

MVP

0.99

MPC

0.27

ClinPred

1.0

D

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.93

Mutation Taster

=2/98

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

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Other links and lift over

dbSNP: rs539743701; hg19: chr12-103260420; API