rs62508624

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. BP4BA1

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: BA1: Highest MAF=0.10514 in 1000G. 35 homozygotes in ExAC; BP4: HSF: No significant splicing motif alteration detected. This mutation has probably no impact on splicing. CADD=1.163344. 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, BP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA180267/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.026 ( 175 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 159 hom. )

Consequence

PAH
NM_000277.3 splice_region, intron

Scores

Splicing: ADA: 0.00003234

Clinical Significance

Benign reviewed by expert panel B:11O:1

Conservation

PhyloP100: -0.536

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.707-7A>T		splice_region_variant, intron_variant	Intron 6 of 12	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.707-7A>T		splice_region_variant, intron_variant	Intron 7 of 13		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 link	c.707-7A>T	splice_region_variant, intron_variant	Intron 6 of 12	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000549247.6 link	n.459A>T	non_coding_transcript_exon_variant	Exon 1 of 6	2
PAH	ENST00000307000.7 link	c.692-7A>T	splice_region_variant, intron_variant	Intron 7 of 13	5		ENSP00000303500.2	J3KND8
PAH	ENST00000635477.1 link	c.-141A>T	upstream_gene_variant		5		ENSP00000489230.1	A0A0U1RQY4

Frequencies

GnomAD3 genomes

AF:

0.0265

AC:

4027

AN:

151974

Hom.:

175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0908

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0110

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.0192

GnomAD2 exomes

AF:

0.00715

AC:

1789

AN:

250224

AF XY:

0.00549

show subpopulations

Gnomad AFR exome

AF:

0.0897

Gnomad AMR exome

AF:

0.00509

Gnomad ASJ exome

AF:

0.00986

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000292

Gnomad OTH exome

AF:

0.00344

GnomAD4 exome

AF:

0.00282

AC:

4115

AN:

1461718

Hom.:

159

Cov.:

AF XY:

0.00252

AC XY:

1831

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.0884

AC:

2959

AN:

33470

American (AMR)

AF:

0.00628

AC:

281

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00876

AC:

229

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.000220

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000168

AC:

187

AN:

1111942

Other (OTH)

AF:

0.00681

AC:

411

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

219

438

656

875

1094

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

192

288

384

480

<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:

0.0265

AC:

4026

AN:

152092

Hom.:

175

Cov.:

AF XY:

0.0249

AC XY:

1849

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0905

AC:

3756

AN:

41480

American (AMR)

AF:

0.0110

AC:

168

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.000208

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000368

AC:

AN:

68006

Other (OTH)

AF:

0.0190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

180

360

540

720

900

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.00930

Hom.:

Bravo

AF:

0.0302

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:11Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:5Other:1

Jul 24, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

May 14, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: c.707-7A>T in PAH gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing pattern, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.008876 (1049/ 118182 chrs tested), predominantly in individuals of African descent (0.08901; 910/ 10224 chrs tested), including 33 homozygotes. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.0079 suggesting that it is a benign polymorphism. The variant of interest has been reported in PKU individuals without strong evidence for causality, but is cited as Benign by a reputable database/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

Feb 02, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely 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

- -

Feb 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 2666653, 27884173) -

Phenylketonuria

Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Aug 10, 2018

ClinGen PAH Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

PAH-specific ACMG/AMP criteria applied: BA1: Highest MAF=0.10514 in 1000G. 35 homozygotes in ExAC; BP4: HSF: No significant splicing motif alteration detected. This mutation has probably no impact on splicing. CADD=1.163344. 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, BP4). -

Nov 14, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 25, 2014

Eurofins Ntd Llc (ga)

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

-0.71

CADD

Benign

5.0

(source)

DANN

Benign

0.68

PhyloP100

-0.54

PromoterAI

0.055

Neutral

(source)

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

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.0

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