12-102846932-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3PM3_StrongPP4_ModeratePM2PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The c.932T>C (p.Leu311Pro) variant in PAH has been reported in multiple individuals with PAH deficiency BH4 defect excluded). (PMID:9634518). This variant has an extremely low allele frequency in gnomAD. This variant has enzyme activity <1% in both standard cDNA and intinic systems. This variant was detected with pathogenic variants I65T (PMID:23842451) p.Y386C (PMID:22841515) p.R261Q (PMID:21871829) c.842+5G>A (PMID:19609714) p.Gly257Asp (PMID:26666653) (parental analysis not reported) and in trans with pathogenic variant c.842+1G>A (PMID:27121329) >2 points. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PP4_Moderate, PS3_supporting, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA251524/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

17

1

Clinical Significance

Pathogenic reviewed by expert panel P:8O:1

Conservation

PhyloP100: 8.94

Publications

21 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 10 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.932T>C	p.Leu311Pro	missense	Exon 9 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.932T>C	p.Leu311Pro	missense	Exon 10 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.932T>C	p.Leu311Pro	missense	Exon 9 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.1031T>C	p.Leu344Pro	missense	Exon 10 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.932T>C	p.Leu311Pro	missense	Exon 9 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

2

AN:

152186

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

5

AN:

251288

AF XY:

0.0000147

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:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

11

AN:

1461478

Hom.:

0

Cov.:

30

AF XY:

0.00000825

AC XY:

6

AN XY:

727072

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

33454

American (AMR)

AF:

0.00

AC:

0

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

0

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000900

AC:

10

AN:

1111696

Other (OTH)

AF:

0.0000166

AC:

1

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.0000131

AC:

2

AN:

152186

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41448

American (AMR)

AF:

0.00

AC:

0

AN:

15276

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:

4832

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

2

AN:

68034

Other (OTH)

AF:

0.00

AC:

0

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000196

Hom.:

0

Bravo

AF:

0.0000113

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)

-

-

-

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.49

D

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

33

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

1.0

D

LIST_S2

Pathogenic

0.99

D

M_CAP

Pathogenic

0.89

D

MetaRNN

Pathogenic

0.98

D

MetaSVM

Pathogenic

0.96

D

MutationAssessor

Pathogenic

4.0

H

PhyloP100

8.9

PrimateAI

Pathogenic

0.82

D

PROVEAN

Pathogenic

-6.8

D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D

Sift4G

Pathogenic

0.0

D

Polyphen

1.0

D

Vest4

0.99

MVP

1.0

MPC

0.28

ClinPred

1.0

D

GERP RS

5.4

Varity_R

0.99

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.13

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: rs62642936; hg19: chr12-103240710; API