rs5030860

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3PM3PM5PS3PP4_Moderate

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM5: c.1240T>C likely pathogenic in ClinVar; PP3: All computational evidence supports deleterious effect. REVEL=0.982; PS3: 50% activity, 50% immunoreactivity (PMID:2044609); PM3_VeryStrong: Patient #41 p.R408W / p.Y414C, Phe 744 @dx and two homozygous individuals. Total of 9 patients with this variant (PMID:22526846; PMID:17935162; PMID:9399896; PMID:21871829; PMID:26542770); PP4_Moderate: BH4 defect excluded in all patients (PMID:22526846). 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: (PM5, PP3, PS3, PM3_VeryStrong, PP4_Moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA114362/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 1 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

14

4

Clinical Significance

Pathogenic reviewed by expert panel P:29O:1

Conservation

PhyloP100: 7.63

Publications

83 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

Specifications for PAH are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS3

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.1241A>G	p.Tyr414Cys	missense	Exon 12 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.1241A>G	p.Tyr414Cys	missense	Exon 13 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.1241A>G	p.Tyr414Cys	missense	Exon 12 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.1340A>G	p.Tyr447Cys	missense	Exon 13 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.1319A>G	p.Tyr440Cys	missense	Exon 12 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

39

AN:

152202

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000558

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000366

AC:

92

AN:

251440

AF XY:

0.000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000721

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000365

AC:

533

AN:

1461726

Hom.:

1

Cov.:

31

AF XY:

0.000375

AC XY:

273

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.0000896

AC:

3

AN:

33472

American (AMR)

AF:

0.000179

AC:

8

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86258

European-Finnish (FIN)

AF:

0.000168

AC:

9

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5766

European-Non Finnish (NFE)

AF:

0.000443

AC:

493

AN:

1111874

Other (OTH)

AF:

0.000331

AC:

20

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0

26

52

78

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

20

40

60

80

100

<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:

0.000256

AC:

39

AN:

152320

Hom.:

0

Cov.:

32

AF XY:

0.000175

AC XY:

13

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41560

American (AMR)

AF:

0.00

AC:

0

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4820

European-Finnish (FIN)

AF:

0.0000941

AC:

1

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

294

European-Non Finnish (NFE)

AF:

0.000558

AC:

38

AN:

68040

Other (OTH)

AF:

0.00

AC:

0

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0

2

4

6

8

10

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:

0.000426

Hom.:

3

Bravo

AF:

0.000246

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000465

AC:

4

ExAC

AF:

0.000494

AC:

60

Asia WGS

AF:

0.000289

AC:

2

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000296

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

18

-

-

Phenylketonuria (18)

7

-

-

not provided (8)

2

-

-

PAH-related disorder (2)

1

-

-

Hyperphenylalaninemia (1)

1

-

-

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.31

D

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

26

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Pathogenic

0.98

D

M_CAP

Pathogenic

0.82

D

MetaRNN

Pathogenic

0.98

D

MetaSVM

Pathogenic

0.96

D

MutationAssessor

Pathogenic

4.3

H

PhyloP100

7.6

PrimateAI

Uncertain

0.65

T

PROVEAN

Pathogenic

-8.1

D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

D

Sift4G

Pathogenic

0.0010

D

Polyphen

1.0

D

Vest4

0.98

MVP

0.99

MPC

0.26

ClinPred

0.94

D

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.96

Mutation Taster

=0/100

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Other links and lift over

dbSNP: rs5030860; hg19: chr12-103234252; API

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