rs74503222

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 7 ACMG points: 7P and 0B. PP3PM3PP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: Absent from 1000G, ESP. Extremely low frequency in ExAC and gnomAD (0.00004065); PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.981; PP4_Moderate: L249F was seen 3 times in HPA patients associated with 2 different haplotypes. DHPR defeciency was excluded. Upgraded per ClinGen Metabolic workgroup. (PMID:8533759); PM3_VeryStrong: Seen with R261X, A309V, V388M, R261Q. All Pathogenic/Likely Pathogenic in ClinVar. Upgraded per ClinGen SVI Workgroup (PMID:21871829; PMID:24765287). 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, PP4_Moderate, PM3_VeryStrong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA273356/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:11O:1

Conservation

PhyloP100: 8.15

Publications

20 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 7 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.

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.745C>T	p.Leu249Phe	missense	Exon 7 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.745C>T	p.Leu249Phe	missense	Exon 8 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAH	ENST00000553106.6	TSL:1 MANE Select	c.745C>T	p.Leu249Phe	missense	Exon 7 of 13	ENSP00000448059.1	P00439
PAH	ENST00000906695.1		c.745C>T	p.Leu249Phe	missense	Exon 7 of 14	ENSP00000576754.1
PAH	ENST00000906692.1		c.745C>T	p.Leu249Phe	missense	Exon 7 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251222

AF XY:

0.0000442

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:

0.000139

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000705

AC:

103

AN:

1461850

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000827

AC:

AN:

1111992

Other (OTH)

AF:

0.000149

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000394

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41432

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000593

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Phenylketonuria (7)

not provided (5)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

4.1

PhyloP100

8.2

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.91

MutPred

0.90

Gain of catalytic residue at L249 (P = 0.0553)

MVP

0.98

MPC

0.25

ClinPred

0.99

GERP RS

5.0

PromoterAI

0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.97

gMVP

0.95

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over