NM_000277.3:c.913-341A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000277.3(PAH):​c.913-341A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.863 in 358,714 control chromosomes in the GnomAD database, including 133,868 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 0.86 ( 55983 hom., cov: 32)
Exomes 𝑓: 0.87 ( 77885 hom. )

Consequence

PAH
NM_000277.3 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.710

Publications

3 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.93).
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAHNM_000277.3 linkc.913-341A>G intron_variant Intron 8 of 12 ENST00000553106.6 NP_000268.1 P00439A0A024RBG4
PAHNM_001354304.2 linkc.913-341A>G intron_variant Intron 9 of 13 NP_001341233.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAHENST00000553106.6 linkc.913-341A>G intron_variant Intron 8 of 12 1 NM_000277.3 ENSP00000448059.1 P00439

Frequencies

GnomAD3 genomes
AF:
0.857
AC:
130354
AN:
152086
Hom.:
55942
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.845
Gnomad AMI
AF:
0.794
Gnomad AMR
AF:
0.890
Gnomad ASJ
AF:
0.826
Gnomad EAS
AF:
0.850
Gnomad SAS
AF:
0.916
Gnomad FIN
AF:
0.907
Gnomad MID
AF:
0.842
Gnomad NFE
AF:
0.849
Gnomad OTH
AF:
0.857
GnomAD4 exome
AF:
0.868
AC:
179163
AN:
206510
Hom.:
77885
Cov.:
0
AF XY:
0.873
AC XY:
96110
AN XY:
110118
show subpopulations
African (AFR)
AF:
0.845
AC:
5417
AN:
6414
American (AMR)
AF:
0.898
AC:
9946
AN:
11072
Ashkenazi Jewish (ASJ)
AF:
0.836
AC:
4614
AN:
5516
East Asian (EAS)
AF:
0.851
AC:
8974
AN:
10540
South Asian (SAS)
AF:
0.924
AC:
30276
AN:
32764
European-Finnish (FIN)
AF:
0.908
AC:
8667
AN:
9546
Middle Eastern (MID)
AF:
0.838
AC:
657
AN:
784
European-Non Finnish (NFE)
AF:
0.851
AC:
101132
AN:
118882
Other (OTH)
AF:
0.862
AC:
9480
AN:
10992
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.509
Heterozygous variant carriers
0
1138
2277
3415
4554
5692
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
548
1096
1644
2192
2740
<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:
0.857
AC:
130452
AN:
152204
Hom.:
55983
Cov.:
32
AF XY:
0.862
AC XY:
64133
AN XY:
74416
show subpopulations
African (AFR)
AF:
0.845
AC:
35082
AN:
41536
American (AMR)
AF:
0.890
AC:
13599
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.826
AC:
2869
AN:
3472
East Asian (EAS)
AF:
0.850
AC:
4389
AN:
5166
South Asian (SAS)
AF:
0.915
AC:
4418
AN:
4828
European-Finnish (FIN)
AF:
0.907
AC:
9608
AN:
10596
Middle Eastern (MID)
AF:
0.847
AC:
249
AN:
294
European-Non Finnish (NFE)
AF:
0.849
AC:
57709
AN:
68012
Other (OTH)
AF:
0.858
AC:
1810
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
967
1934
2902
3869
4836
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
896
1792
2688
3584
4480
<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:
0.847
Hom.:
69361
Bravo
AF:
0.852
Asia WGS
AF:
0.867
AC:
3019
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.93
CADD
Benign
4.0
DANN
Benign
0.78
PhyloP100
-0.71
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs1722387; hg19: chr12-103241070; API