rs1718301

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: This c.441+47C>T variant in PAH is widely found in population databases at a frequency of 0.372401 in ExAC. This intronic variant is not predicted to have a splice-altering consequence. In summary, this variant meets criteria to be classified as a benign for PAH. PAH-specific ACMG/AMP criteria applied: BP7, BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229547/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.38 ( 11349 hom., cov: 30)

Exomes 𝑓: 0.41 ( 99780 hom. )

Consequence

PAH
NM_000277.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:7O:1

Conservation

PhyloP100: -1.57

Publications

11 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.441+47C>T	intron_variant	Intron 4 of 12	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.441+47C>T	intron_variant	Intron 5 of 13		NP_001341233.1
PAH	XM_017019370.2 link	c.441+47C>T	intron_variant	Intron 4 of 6		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.808-2464G>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.441+47C>T		intron_variant	Intron 4 of 12	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.376

AC:

56924

AN:

151588

Hom.:

11340

Cov.:

show subpopulations

Gnomad AFR

AF:

0.287

Gnomad AMI

AF:

0.422

Gnomad AMR

AF:

0.318

Gnomad ASJ

AF:

0.325

Gnomad EAS

AF:

0.116

Gnomad SAS

AF:

0.349

Gnomad FIN

AF:

0.545

Gnomad MID

AF:

0.411

Gnomad NFE

AF:

0.439

Gnomad OTH

AF:

0.379

GnomAD2 exomes

AF:

0.372

AC:

93499

AN:

251282

AF XY:

0.379

show subpopulations

Gnomad AFR exome

AF:

0.283

Gnomad AMR exome

AF:

0.259

Gnomad ASJ exome

AF:

0.335

Gnomad EAS exome

AF:

0.103

Gnomad FIN exome

AF:

0.531

Gnomad NFE exome

AF:

0.437

Gnomad OTH exome

AF:

0.385

GnomAD4 exome

AF:

0.414

AC:

462000

AN:

1116288

Hom.:

99780

Cov.:

AF XY:

0.413

AC XY:

236451

AN XY:

572126

show subpopulations

African (AFR)

AF:

0.285

AC:

7657

AN:

26878

American (AMR)

AF:

0.270

AC:

11968

AN:

44308

Ashkenazi Jewish (ASJ)

AF:

0.336

AC:

8055

AN:

23964

East Asian (EAS)

AF:

0.134

AC:

5106

AN:

38078

South Asian (SAS)

AF:

0.368

AC:

29234

AN:

79380

European-Finnish (FIN)

AF:

0.531

AC:

28238

AN:

53214

Middle Eastern (MID)

AF:

0.412

AC:

2125

AN:

5152

European-Non Finnish (NFE)

AF:

0.440

AC:

350064

AN:

796030

Other (OTH)

AF:

0.397

AC:

19553

AN:

49284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

15553

31106

46660

62213

77766

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8780

17560

26340

35120

43900

<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:

0.375

AC:

56951

AN:

151706

Hom.:

11349

Cov.:

AF XY:

0.378

AC XY:

27999

AN XY:

74090

show subpopulations

African (AFR)

AF:

0.286

AC:

11831

AN:

41352

American (AMR)

AF:

0.318

AC:

4858

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.325

AC:

1125

AN:

3466

East Asian (EAS)

AF:

0.116

AC:

595

AN:

5126

South Asian (SAS)

AF:

0.351

AC:

1681

AN:

4794

European-Finnish (FIN)

AF:

0.545

AC:

5717

AN:

10498

Middle Eastern (MID)

AF:

0.408

AC:

119

AN:

292

European-Non Finnish (NFE)

AF:

0.439

AC:

29835

AN:

67898

Other (OTH)

AF:

0.381

AC:

805

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1753

3506

5258

7011

8764

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

554

1108

1662

2216

2770

<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:

0.397

Hom.:

7013

Bravo

AF:

0.354

Asia WGS

AF:

0.264

AC:

918

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Benign:4

Oct 27, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Dec 09, 2022

ClinGen PAH Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

This c.441+47C>T variant in PAH is widely found in population databases at a frequency of 0.372401 in ExAC. This intronic variant is not predicted to have a splice-altering consequence. In summary, this variant meets criteria to be classified as a benign for PAH. PAH-specific ACMG/AMP criteria applied: BP7, BA1. -

not provided

Benign:2Other:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

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

-0.83

CADD

Benign

0.30

(source)

DANN

Benign

0.72

PhyloP100

-1.6

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)

0.010

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