NM_000277.3:c.60+62C>T

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: The c.60+62C>T intronic variant in PAH has a MAF of 0.3441 in gnomAD with 2,014 homozygotes.In summary, this variant meets criteria to be classified as benign for PAH. PAH-specific ACMG/AMP criteria applied: BA1, BS2, BP7. LINK:https://erepo.genome.network/evrepo/ui/classification/CA13630270/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.37 ( 11390 hom., cov: 33)

Exomes 𝑓: 0.32 ( 69576 hom. )

Consequence

PAH
NM_000277.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel P:1B:11

Conservation

PhyloP100: -0.508

Publications

15 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	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.60+62C>T	intron_variant	Intron 1 of 12	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.60+62C>T	intron_variant	Intron 2 of 13		NP_001341233.1
PAH	XM_017019370.2 link	c.60+62C>T	intron_variant	Intron 1 of 6		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.60+62C>T		intron_variant	Intron 1 of 12	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.372

AC:

56513

AN:

151900

Hom.:

11360

Cov.:

show subpopulations

Gnomad AFR

AF:

0.502

Gnomad AMI

AF:

0.314

Gnomad AMR

AF:

0.477

Gnomad ASJ

AF:

0.371

Gnomad EAS

AF:

0.221

Gnomad SAS

AF:

0.314

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.296

Gnomad NFE

AF:

0.315

Gnomad OTH

AF:

0.371

GnomAD4 exome

AF:

0.320

AC:

416270

AN:

1299882

Hom.:

69576

AF XY:

0.318

AC XY:

208511

AN XY:

655128

show subpopulations

African (AFR)

AF:

0.506

AC:

15332

AN:

30282

American (AMR)

AF:

0.525

AC:

23360

AN:

44502

Ashkenazi Jewish (ASJ)

AF:

0.353

AC:

8878

AN:

25122

East Asian (EAS)

AF:

0.224

AC:

8710

AN:

38930

South Asian (SAS)

AF:

0.305

AC:

25314

AN:

82910

European-Finnish (FIN)

AF:

0.199

AC:

10604

AN:

53188

Middle Eastern (MID)

AF:

0.297

AC:

1630

AN:

5484

European-Non Finnish (NFE)

AF:

0.316

AC:

304479

AN:

964366

Other (OTH)

AF:

0.326

AC:

17963

AN:

55098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

15137

30274

45410

60547

75684

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9558

19116

28674

38232

47790

<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:

0.372

AC:

56582

AN:

152018

Hom.:

11390

Cov.:

AF XY:

0.369

AC XY:

27407

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.502

AC:

20796

AN:

41420

American (AMR)

AF:

0.477

AC:

7286

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.371

AC:

1287

AN:

3470

East Asian (EAS)

AF:

0.221

AC:

1138

AN:

5158

South Asian (SAS)

AF:

0.316

AC:

1521

AN:

4820

European-Finnish (FIN)

AF:

0.192

AC:

2027

AN:

10584

Middle Eastern (MID)

AF:

0.277

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.315

AC:

21385

AN:

67962

Other (OTH)

AF:

0.367

AC:

775

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1744

3487

5231

6974

8718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

530

1060

1590

2120

2650

<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:

0.244

Hom.:

787

Bravo

AF:

0.400

Asia WGS

AF:

0.296

AC:

1031

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:11

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:1Benign:5

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

NG_008690.2(NM_000277.2):c.60+62C>T in the gene PAH has an allele frequency of 0.496 in African subpopulation in the gnomAD database. A total of 2014 homozygous occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2. -

Jun 26, 2018

Clinical Laboratory, Xuzhou Maternity and Child Health Care Hospital

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:case-control

- -

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

African/African American population allele frequency is 48.34% (rs1522296, 4299/8672 alleles, 1055 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

Jul 01, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 08, 2019

ClinGen PAH Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The c.60+62C>T intronic variant in PAH has a MAF of 0.3441 in gnomAD with 2,014 homozygotes.In summary, this variant meets criteria to be classified as benign for PAH. PAH-specific ACMG/AMP criteria applied: BA1, BS2, BP7. -

Apr 23, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 28, 2020

H3Africa Consortium

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.521, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

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

- -

PAH-related disorder

Benign:1

Feb 18, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.98

(source)

DANN

Benign

0.43

PhyloP100

-0.51

PromoterAI

-0.0090

Neutral

(source)

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