12-102846852-C-A

Variant names:

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=0.49022 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/CA145984/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.36 ( 10523 hom., cov: 32)

Exomes 𝑓: 0.40 ( 116538 hom. )

Consequence

PAH
NM_000277.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:6O:1

Conservation

PhyloP100: -1.11

Publications

6 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 -8 ACMG points.

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.969+43G>T		intron_variant	Intron 9 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 link	c.969+43G>T		intron_variant	Intron 10 of 13		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.969+43G>T		intron_variant	Intron 9 of 12	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes

AF:

0.360

AC:

54663

AN:

151902

Hom.:

10514

Cov.:

show subpopulations

Gnomad AFR

AF:

0.273

Gnomad AMI

AF:

0.420

Gnomad AMR

AF:

0.313

Gnomad ASJ

AF:

0.319

Gnomad EAS

AF:

0.0550

Gnomad SAS

AF:

0.332

Gnomad FIN

AF:

0.508

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.426

Gnomad OTH

AF:

0.366

GnomAD2 exomes

AF:

0.351

AC:

88020

AN:

250424

AF XY:

0.359

show subpopulations

Gnomad AFR exome

AF:

0.270

Gnomad AMR exome

AF:

0.244

Gnomad ASJ exome

AF:

0.328

Gnomad EAS exome

AF:

0.0555

Gnomad FIN exome

AF:

0.490

Gnomad NFE exome

AF:

0.421

Gnomad OTH exome

AF:

0.367

GnomAD4 exome

AF:

0.403

AC:

555142

AN:

1377846

Hom.:

116538

Cov.:

AF XY:

0.402

AC XY:

277660

AN XY:

690566

show subpopulations

African (AFR)

AF:

0.269

AC:

8501

AN:

31618

American (AMR)

AF:

0.255

AC:

11357

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.330

AC:

8445

AN:

25618

East Asian (EAS)

AF:

0.0463

AC:

1818

AN:

39276

South Asian (SAS)

AF:

0.349

AC:

29491

AN:

84598

European-Finnish (FIN)

AF:

0.487

AC:

25978

AN:

53338

Middle Eastern (MID)

AF:

0.392

AC:

2186

AN:

5580

European-Non Finnish (NFE)

AF:

0.430

AC:

445235

AN:

1035596

Other (OTH)

AF:

0.384

AC:

22131

AN:

57654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

16167

32334

48501

64668

80835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12904

25808

38712

51616

64520

<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:

0.360

AC:

54701

AN:

152020

Hom.:

10523

Cov.:

AF XY:

0.363

AC XY:

26937

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.273

AC:

11332

AN:

41450

American (AMR)

AF:

0.312

AC:

4774

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.319

AC:

1106

AN:

3472

East Asian (EAS)

AF:

0.0552

AC:

286

AN:

5184

South Asian (SAS)

AF:

0.334

AC:

1603

AN:

4806

European-Finnish (FIN)

AF:

0.508

AC:

5354

AN:

10544

Middle Eastern (MID)

AF:

0.398

AC:

117

AN:

294

European-Non Finnish (NFE)

AF:

0.426

AC:

28969

AN:

67962

Other (OTH)

AF:

0.368

AC:

777

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1726

3453

5179

6906

8632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

534

1068

1602

2136

2670

<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:

0.395

Hom.:

3998

Bravo

AF:

0.340

Asia WGS

AF:

0.233

AC:

810

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 22, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Phenylketonuria

Benign:2

Jul 01, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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: MAF=0.49022 in ExAC; BP2: Observed in cis with R261Q. (PMID:24048906). 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, BP2). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.28

(source)

DANN

Benign

0.77

PhyloP100

-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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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