rs2037639

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1BP7

This summary comes from the ClinGen Evidence Repository: The c.353-22C>T variant in PAH has a MAF of 0.7066 in the gnomAD East Asian population. This intronic variant does not have a predicted impact on splicing. In summary this variant meets criteria to be classified as benign. PAH-specific ACMG/AMP criteria applied: BA1, BP7 LINK:https://erepo.genome.network/evrepo/ui/classification/CA229520/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.22 ( 4517 hom., cov: 31)

Exomes 𝑓: 0.25 ( 48672 hom. )

Consequence

PAH
NM_000277.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:8O:1

Conservation

PhyloP100: -0.216

Publications

12 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), G2P, ClinGen, Myriad Women’s Health
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:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP7

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.353-22C>T	intron_variant	Intron 3 of 12	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.353-22C>T	intron_variant	Intron 4 of 13		NP_001341233.1
PAH	XM_017019370.2 link	c.353-22C>T	intron_variant	Intron 3 of 6		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.808-2307G>A	intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.353-22C>T		intron_variant	Intron 3 of 12	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.221

AC:

33548

AN:

151976

Hom.:

4519

Cov.:

show subpopulations

Gnomad AFR

AF:

0.129

Gnomad AMI

AF:

0.265

Gnomad AMR

AF:

0.190

Gnomad ASJ

AF:

0.277

Gnomad EAS

AF:

0.690

Gnomad SAS

AF:

0.335

Gnomad FIN

AF:

0.259

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.230

Gnomad OTH

AF:

0.233

GnomAD2 exomes

AF:

0.274

AC:

68767

AN:

250962

AF XY:

0.278

show subpopulations

Gnomad AFR exome

AF:

0.124

Gnomad AMR exome

AF:

0.191

Gnomad ASJ exome

AF:

0.274

Gnomad EAS exome

AF:

0.707

Gnomad FIN exome

AF:

0.265

Gnomad NFE exome

AF:

0.237

Gnomad OTH exome

AF:

0.263

GnomAD4 exome

AF:

0.247

AC:

352222

AN:

1425802

Hom.:

48672

Cov.:

AF XY:

0.250

AC XY:

178113

AN XY:

711592

show subpopulations

African (AFR)

AF:

0.120

AC:

3930

AN:

32788

American (AMR)

AF:

0.189

AC:

8437

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.280

AC:

7244

AN:

25908

East Asian (EAS)

AF:

0.680

AC:

26906

AN:

39540

South Asian (SAS)

AF:

0.329

AC:

28180

AN:

85578

European-Finnish (FIN)

AF:

0.266

AC:

14203

AN:

53348

Middle Eastern (MID)

AF:

0.273

AC:

1556

AN:

5706

European-Non Finnish (NFE)

AF:

0.228

AC:

246332

AN:

1079078

Other (OTH)

AF:

0.261

AC:

15434

AN:

59196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

12561

25122

37682

50243

62804

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8510

17020

25530

34040

42550

<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:

0.221

AC:

33549

AN:

152092

Hom.:

4517

Cov.:

AF XY:

0.224

AC XY:

16679

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.129

AC:

5350

AN:

41518

American (AMR)

AF:

0.190

AC:

2907

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.277

AC:

962

AN:

3470

East Asian (EAS)

AF:

0.690

AC:

3556

AN:

5150

South Asian (SAS)

AF:

0.333

AC:

1603

AN:

4812

European-Finnish (FIN)

AF:

0.259

AC:

2740

AN:

10566

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.230

AC:

15615

AN:

67978

Other (OTH)

AF:

0.234

AC:

492

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1264

2528

3791

5055

6319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

366

732

1098

1464

1830

<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:

0.214

Hom.:

5372

Bravo

AF:

0.214

Asia WGS

AF:

0.432

AC:

1504

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Benign:5

May 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 27, 2020

ClinGen PAH Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.353-22C>T variant in PAH has a MAF of 0.7066 in the gnomAD East Asian population. This intronic variant does not have a predicted impact on splicing. In summary this variant meets criteria to be classified as benign. PAH-specific ACMG/AMP criteria applied: BA1, BP7 -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.1

(source)

DANN

Benign

0.60

PhyloP100

-0.22

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over