Genetic Variant PAH:c.168+19T>C (chr12-102912772-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: BA1: MAF=0.44942 in ExAC. In summary this variant meets criteria to be classified as benign for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA145980/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.21 ( 3946 hom., cov: 32)

Exomes 𝑓: 0.17 ( 22653 hom. )

Consequence

PAH
NM_000277.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:12O:1

Conservation

PhyloP100: 2.01

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

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

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.168+19T>C		intron	N/A	NP_000268.1	P00439
	PAH	NM_001354304.2		c.168+19T>C		intron	N/A	NP_001341233.1	P00439

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PAH	ENST00000553106.6	TSL:1 MANE Select	c.168+19T>C	intron	N/A	ENSP00000448059.1	P00439
PAH	ENST00000549111.5	TSL:1	n.264+19T>C	intron	N/A
PAH	ENST00000906695.1		c.168+19T>C	intron	N/A	ENSP00000576754.1

Frequencies

GnomAD3 genomes

AF:

0.210

AC:

31878

AN:

151974

Hom.:

3939

Cov.:

show subpopulations

Gnomad AFR

AF:

0.292

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.344

Gnomad ASJ

AF:

0.224

Gnomad EAS

AF:

0.0845

Gnomad SAS

AF:

0.202

Gnomad FIN

AF:

0.0872

Gnomad MID

AF:

0.123

Gnomad NFE

AF:

0.160

Gnomad OTH

AF:

0.198

GnomAD2 exomes

AF:

0.202

AC:

50662

AN:

251168

AF XY:

0.191

show subpopulations

Gnomad AFR exome

AF:

0.296

Gnomad AMR exome

AF:

0.441

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.0824

Gnomad FIN exome

AF:

0.0960

Gnomad NFE exome

AF:

0.155

Gnomad OTH exome

AF:

0.190

GnomAD4 exome

AF:

0.171

AC:

231573

AN:

1357404

Hom.:

22653

Cov.:

AF XY:

0.169

AC XY:

115544

AN XY:

681788

show subpopulations

African (AFR)

AF:

0.292

AC:

9147

AN:

31368

American (AMR)

AF:

0.428

AC:

19052

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.215

AC:

5495

AN:

25510

East Asian (EAS)

AF:

0.0926

AC:

3625

AN:

39142

South Asian (SAS)

AF:

0.199

AC:

16790

AN:

84188

European-Finnish (FIN)

AF:

0.0978

AC:

5209

AN:

53286

Middle Eastern (MID)

AF:

0.138

AC:

772

AN:

5586

European-Non Finnish (NFE)

AF:

0.159

AC:

161490

AN:

1016850

Other (OTH)

AF:

0.176

AC:

9993

AN:

56912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

9002

18003

27005

36006

45008

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5782

11564

17346

23128

28910

<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:

0.210

AC:

31892

AN:

152094

Hom.:

3946

Cov.:

AF XY:

0.209

AC XY:

15510

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.292

AC:

12084

AN:

41452

American (AMR)

AF:

0.344

AC:

5262

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

776

AN:

3466

East Asian (EAS)

AF:

0.0841

AC:

436

AN:

5186

South Asian (SAS)

AF:

0.203

AC:

978

AN:

4820

European-Finnish (FIN)

AF:

0.0872

AC:

924

AN:

10596

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.160

AC:

10882

AN:

67974

Other (OTH)

AF:

0.196

AC:

413

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1270

2540

3809

5079

6349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

324

648

972

1296

1620

<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:

0.184

Hom.:

3866

Bravo

AF:

0.230

Asia WGS

AF:

0.172

AC:

601

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Phenylketonuria (7)

not specified (3)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.64

PhyloP100

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

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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