12-102851709-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP3PS3PM3_StrongPP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: The c.890G>A (p.Arg297His) variant in PAH has been reported in 6 patients with PKU, in trans with established pathogenic variants (PMID:9298832,24401910) with BH4 deficiency excluded in one (PMIDs 24401910 & 9298832). This variant has an extremely low allele frequency in gnomAD (2/245792). The arginine at position 297 is in the C-terminal aromatic amino acid hydroxylase domain, and computational prediction tools and conservation analysis suggest that the c.890G>A variant may impact the protein function. Mutant enzyme activity is 20% as compared to wild type (PMID:24401910). Overall, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4_moderate, PM2, PM3_strong, PS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA220590/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

6

9

3

Clinical Significance

Pathogenic reviewed by expert panel P:11O:1

Conservation

PhyloP100: 3.05

Publications

10 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 13 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.890G>A	p.Arg297His	missense	Exon 8 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.890G>A	p.Arg297His	missense	Exon 9 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.890G>A	p.Arg297His	missense	Exon 8 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.989G>A	p.Arg330His	missense	Exon 9 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.890G>A	p.Arg297His	missense	Exon 8 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

4

AN:

152130

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00000398

AC:

1

AN:

251036

AF XY:

0.00000737

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

35

AN:

1461638

Hom.:

0

Cov.:

30

AF XY:

0.0000206

AC XY:

15

AN XY:

727122

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33470

American (AMR)

AF:

0.00

AC:

0

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

2

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000288

AC:

32

AN:

1111836

Other (OTH)

AF:

0.0000166

AC:

1

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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

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:

0.0000263

AC:

4

AN:

152130

Hom.:

0

Cov.:

32

AF XY:

0.0000269

AC XY:

2

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.0000241

AC:

1

AN:

41426

American (AMR)

AF:

0.0000655

AC:

1

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

1

AN:

68030

Other (OTH)

AF:

0.000478

AC:

1

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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:

0.0000210

Hom.:

0

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

1

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

8

-

-

Phenylketonuria (8)

2

-

-

not provided (3)

1

-

-

Hyperphenylalaninemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.19

D

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

30

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

D

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.84

D

LIST_S2

Uncertain

0.94

D

M_CAP

Pathogenic

0.39

D

MetaRNN

Pathogenic

0.97

D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Benign

1.6

L

PhyloP100

3.0

PrimateAI

Uncertain

0.63

T

PROVEAN

Benign

-0.51

N

REVEL

Uncertain

0.64

Sift

Uncertain

0.011

D

Sift4G

Uncertain

0.014

D

Polyphen

0.94

P

Vest4

0.83

MutPred

0.90

Gain of disorder (P = 0.1384)

MVP

0.98

MPC

0.13

ClinPred

0.83

D

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.89

Mutation Taster

=15/85

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.040

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: rs62642939; hg19: chr12-103245487; COSMIC: COSV100187604; COSMIC: COSV100187604; API