12-102843690-G-C

Variant names:

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.1155C>G (p.Leu385=) synonymous variant in PAH is not predicted to have a splice-altering consequence. This variant was present at a high frequency of 0.840256 in 1000 genomes and 0.858145 in ExAC. 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/CA180265/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.84 ( 53986 hom., cov: 29)

Exomes 𝑓: 0.85 ( 528935 hom. )

Consequence

PAH
NM_000277.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: -0.0970

Publications

34 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.

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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.1155C>G	p.Leu385Leu	synonymous_variant	Exon 11 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.1155C>G	p.Leu385Leu	synonymous_variant	Exon 12 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.1155C>G	p.Leu385Leu	synonymous_variant	Exon 11 of 13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.842

AC:

127910

AN:

151868

Hom.:

53951

Cov.:

show subpopulations

Gnomad AFR

AF:

0.804

Gnomad AMI

AF:

0.792

Gnomad AMR

AF:

0.885

Gnomad ASJ

AF:

0.820

Gnomad EAS

AF:

0.840

Gnomad SAS

AF:

0.872

Gnomad FIN

AF:

0.907

Gnomad MID

AF:

0.832

Gnomad NFE

AF:

0.846

Gnomad OTH

AF:

0.844

GnomAD2 exomes

AF:

0.861

AC:

216427

AN:

251268

AF XY:

0.860

show subpopulations

Gnomad AFR exome

AF:

0.799

Gnomad AMR exome

AF:

0.913

Gnomad ASJ exome

AF:

0.822

Gnomad EAS exome

AF:

0.839

Gnomad FIN exome

AF:

0.907

Gnomad NFE exome

AF:

0.847

Gnomad OTH exome

AF:

0.851

GnomAD4 exome

AF:

0.851

AC:

1242694

AN:

1461134

Hom.:

528935

Cov.:

AF XY:

0.852

AC XY:

619004

AN XY:

726890

show subpopulations

African (AFR)

AF:

0.802

AC:

26836

AN:

33450

American (AMR)

AF:

0.908

AC:

40567

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.823

AC:

21502

AN:

26130

East Asian (EAS)

AF:

0.846

AC:

33568

AN:

39696

South Asian (SAS)

AF:

0.889

AC:

76662

AN:

86246

European-Finnish (FIN)

AF:

0.910

AC:

48602

AN:

53406

Middle Eastern (MID)

AF:

0.857

AC:

4937

AN:

5762

European-Non Finnish (NFE)

AF:

0.845

AC:

938782

AN:

1111384

Other (OTH)

AF:

0.849

AC:

51238

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

9848

19696

29545

39393

49241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21122

42244

63366

84488

105610

<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:

0.842

AC:

128004

AN:

151986

Hom.:

53986

Cov.:

AF XY:

0.847

AC XY:

62900

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.804

AC:

33295

AN:

41430

American (AMR)

AF:

0.885

AC:

13510

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.820

AC:

2846

AN:

3472

East Asian (EAS)

AF:

0.840

AC:

4325

AN:

5148

South Asian (SAS)

AF:

0.872

AC:

4187

AN:

4802

European-Finnish (FIN)

AF:

0.907

AC:

9597

AN:

10586

Middle Eastern (MID)

AF:

0.844

AC:

248

AN:

294

European-Non Finnish (NFE)

AF:

0.846

AC:

57487

AN:

67966

Other (OTH)

AF:

0.845

AC:

1787

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1020

2040

3059

4079

5099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

890

1780

2670

3560

4450

<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:

0.839

Hom.:

13908

Bravo

AF:

0.837

EpiCase

AF:

0.834

EpiControl

AF:

0.837

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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.1155C>G (p.Leu385=) synonymous variant in PAH is not predicted to have a splice-altering consequence. This variant was present at a high frequency of 0.840256 in 1000 genomes and 0.858145 in ExAC. In summary, this variant meets criteria to be classified as a benign for PAH. PAH-specific ACMG/AMP criteria applied: BP7, BA1. -

Nov 16, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

May 16, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

2.2

(source)

DANN

Benign

0.60

PhyloP100

-0.097

Mutation Taster

=99/1

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