dbSNP rs62509021: PAH:c.1316-35C>T (chr12-102839253-G-A) – ACMG Classification: Benign (-9 pts)

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.1316-35C>T variant in PAH has a MAF of 0.02321 in the gnomAD European (Non-Finnish) population. This intronic variant does not have a predicted impact on splicing. In summary this variant meets criteria to be classified as benign. PAH-specific ACMG/AMP criteria applied: BA1, BP7 LINK:https://erepo.genome.network/evrepo/ui/classification/CA229433/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.017 ( 34 hom., cov: 33)

Exomes 𝑓: 0.022 ( 444 hom. )

Consequence

PAH
NM_000277.3 intron

Scores

Clinical Significance

Benign reviewed by expert panel B:5O:1

Conservation

PhyloP100: -1.87

Publications

4 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), ClinGen, Myriad Women’s Health, G2P
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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.1316-35C>T		intron	N/A	NP_000268.1	P00439
	PAH	NM_001354304.2		c.1316-35C>T		intron	N/A	NP_001341233.1	P00439

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PAH	ENST00000553106.6	TSL:1 MANE Select	c.1316-35C>T	intron	N/A	ENSP00000448059.1	P00439
PAH	ENST00000906695.1		c.1415-35C>T	intron	N/A	ENSP00000576754.1
PAH	ENST00000906692.1		c.1394-35C>T	intron	N/A	ENSP00000576751.1

Frequencies

GnomAD3 genomes

AF:

0.0167

AC:

2543

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00461

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0207

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0255

Gnomad OTH

AF:

0.0196

GnomAD2 exomes

AF:

0.0161

AC:

4031

AN:

250524

AF XY:

0.0168

show subpopulations

Gnomad AFR exome

AF:

0.00329

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.0189

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00977

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0182

GnomAD4 exome

AF:

0.0223

AC:

32486

AN:

1455256

Hom.:

444

Cov.:

AF XY:

0.0222

AC XY:

16076

AN XY:

724472

show subpopulations

African (AFR)

AF:

0.00354

AC:

118

AN:

33328

American (AMR)

AF:

0.0145

AC:

646

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.0160

AC:

416

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.0136

AC:

1167

AN:

86106

European-Finnish (FIN)

AF:

0.00974

AC:

518

AN:

53210

Middle Eastern (MID)

AF:

0.0181

AC:

104

AN:

5760

European-Non Finnish (NFE)

AF:

0.0254

AC:

28119

AN:

1106280

Other (OTH)

AF:

0.0232

AC:

1398

AN:

60154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1508

3016

4525

6033

7541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1034

2068

3102

4136

5170

<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:

0.0167

AC:

2542

AN:

152286

Hom.:

Cov.:

AF XY:

0.0156

AC XY:

1163

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00460

AC:

191

AN:

41560

American (AMR)

AF:

0.0207

AC:

316

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5190

South Asian (SAS)

AF:

0.0126

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0101

AC:

107

AN:

10606

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0255

AC:

1733

AN:

68022

Other (OTH)

AF:

0.0194

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

135

269

404

538

673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0220

Hom.:

Bravo

AF:

0.0165

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (1)

Phenylketonuria (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.046

(source)

DANN

Benign

0.20

PhyloP100

-1.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over