Genetic Variant PAH:c.352+4541T>C (chr12-102890194-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_000277.3(PAH):c.352+4541T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 152,204 control chromosomes in the GnomAD database, including 50,478 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.81 ( 50478 hom., cov: 32)

Consequence

PAH
NM_000277.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.691

Publications

7 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:

LOC124902999 (HGNC:):

LOC124902999 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.352+4541T>C	intron_variant	Intron 3 of 12	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.352+4541T>C	intron_variant	Intron 4 of 13		NP_001341233.1
PAH	XM_017019370.2 link	c.352+4541T>C	intron_variant	Intron 3 of 6		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.862+10261A>G	intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.352+4541T>C		intron_variant	Intron 3 of 12	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.808

AC:

122954

AN:

152086

Hom.:

50421

Cov.:

show subpopulations

Gnomad AFR

AF:

0.933

Gnomad AMI

AF:

0.797

Gnomad AMR

AF:

0.820

Gnomad ASJ

AF:

0.759

Gnomad EAS

AF:

0.988

Gnomad SAS

AF:

0.897

Gnomad FIN

AF:

0.677

Gnomad MID

AF:

0.775

Gnomad NFE

AF:

0.734

Gnomad OTH

AF:

0.796

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.809

AC:

123068

AN:

152204

Hom.:

50478

Cov.:

AF XY:

0.808

AC XY:

60123

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.933

AC:

38794

AN:

41562

American (AMR)

AF:

0.820

AC:

12529

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.759

AC:

2636

AN:

3472

East Asian (EAS)

AF:

0.988

AC:

5115

AN:

5176

South Asian (SAS)

AF:

0.898

AC:

4326

AN:

4820

European-Finnish (FIN)

AF:

0.677

AC:

7158

AN:

10580

Middle Eastern (MID)

AF:

0.772

AC:

227

AN:

294

European-Non Finnish (NFE)

AF:

0.734

AC:

49881

AN:

67994

Other (OTH)

AF:

0.795

AC:

1675

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1157

2314

3471

4628

5785

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

870

1740

2610

3480

4350

<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:

0.771

Hom.:

92784

Bravo

AF:

0.821

Asia WGS

AF:

0.909

AC:

3161

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

0.69

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over