12-102855313-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP3PM5PM3_StrongPM2PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.529G>A (p.Val177Met) variant in PAH was detected in a patient with Mild hyperphenylalaninemia (BH4 deficiency ruled out). PMID:12501224 It has been detected with known pathogenic variants R408W (PMID:12501224), and IVS12+1G>A (PMID:23764561). It is absent from 1000G, ESP, and gnomAD; and at extremely low frequency in ExAC (MAF=0.00003). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.89. A different pathogenic missense change has been seen at this amino acid (V177L). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229609/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000049 ( 1 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

12

5

1

Clinical Significance

Pathogenic reviewed by expert panel P:13O:1

Conservation

PhyloP100: 3.39

Publications

14 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.

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.529G>A	p.Val177Met	missense	Exon 6 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.529G>A	p.Val177Met	missense	Exon 7 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.529G>A	p.Val177Met	missense	Exon 6 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000549111.5	TSL:1	n.625G>A		non_coding_transcript_exon	Exon 6 of 6
	PAH	ENST00000906695.1		c.529G>A	p.Val177Met	missense	Exon 6 of 14	ENSP00000576754.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152142

Hom.:

0

Cov.:

33

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:

251188

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000493

AC:

72

AN:

1461830

Hom.:

1

Cov.:

34

AF XY:

0.0000523

AC XY:

38

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.0000299

AC:

1

AN:

33480

American (AMR)

AF:

0.0000224

AC:

1

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

1

AN:

53416

Middle Eastern (MID)

AF:

0.00104

AC:

6

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000531

AC:

59

AN:

1111970

Other (OTH)

AF:

0.0000662

AC:

4

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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

Exome Hom

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:

0.0000131

AC:

2

AN:

152142

Hom.:

0

Cov.:

33

AF XY:

0.00

AC XY:

0

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41418

American (AMR)

AF:

0.00

AC:

0

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4828

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:

68040

Other (OTH)

AF:

0.00

AC:

0

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.0000717

Hom.:

0

Bravo

AF:

0.0000378

ExAC

AF:

0.0000165

AC:

2

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

9

-

-

Phenylketonuria (9)

2

-

-

not provided (3)

1

-

-

Hyperphenylalaninemia (1)

1

-

-

PAH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.40

D

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

26

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.97

D

LIST_S2

Uncertain

0.96

D

M_CAP

Pathogenic

0.46

D

MetaRNN

Pathogenic

0.99

D

MetaSVM

Pathogenic

0.99

D

MutationAssessor

Pathogenic

3.8

H

PhyloP100

3.4

PrimateAI

Uncertain

0.61

T

PROVEAN

Uncertain

-2.6

D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D

Sift4G

Uncertain

0.027

D

Polyphen

0.99

D

Vest4

0.78

MutPred

0.95

Gain of disorder (P = 0.0559)

MVP

0.98

MPC

0.14

ClinPred

0.99

D

GERP RS

4.8

Varity_R

0.85

gMVP

0.91

Mutation Taster

=15/85

disease causing (ClinVar)

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.

Other links and lift over

dbSNP: rs199475602; hg19: chr12-103249091; COSMIC: COSV108133740; COSMIC: COSV108133740; API

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