NM_000277.3:c.913-459T>C
Variant names:
Variant summary
Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1
The NM_000277.3(PAH):c.913-459T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 186,186 control chromosomes in the GnomAD database, including 10,089 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 0.32 ( 8223 hom., cov: 32)
Exomes 𝑓: 0.31 ( 1866 hom. )
Consequence
PAH
NM_000277.3 intron
NM_000277.3 intron
Scores
2
Clinical Significance
Not reported in ClinVar
Conservation
PhyloP100: -0.935
Publications
3 publications found
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):
- phenylketonuriaInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
- classic phenylketonuriaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- maternal phenylketonuriaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- mild hyperphenylalaninemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- mild phenylketonuriaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuriaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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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=-0.97).
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.381 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PAH | NM_000277.3 | c.913-459T>C | intron_variant | Intron 8 of 12 | ENST00000553106.6 | NP_000268.1 | ||
PAH | NM_001354304.2 | c.913-459T>C | intron_variant | Intron 9 of 13 | NP_001341233.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.319 AC: 48423AN: 151954Hom.: 8218 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
48423
AN:
151954
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.306 AC: 10450AN: 34114Hom.: 1866 Cov.: 0 AF XY: 0.303 AC XY: 5312AN XY: 17546 show subpopulations
GnomAD4 exome
AF:
AC:
10450
AN:
34114
Hom.:
Cov.:
0
AF XY:
AC XY:
5312
AN XY:
17546
show subpopulations
African (AFR)
AF:
AC:
320
AN:
1546
American (AMR)
AF:
AC:
941
AN:
3602
Ashkenazi Jewish (ASJ)
AF:
AC:
203
AN:
768
East Asian (EAS)
AF:
AC:
140
AN:
3128
South Asian (SAS)
AF:
AC:
976
AN:
3244
European-Finnish (FIN)
AF:
AC:
286
AN:
816
Middle Eastern (MID)
AF:
AC:
24
AN:
116
European-Non Finnish (NFE)
AF:
AC:
6998
AN:
19226
Other (OTH)
AF:
AC:
562
AN:
1668
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.504
Heterozygous variant carriers
0
314
627
941
1254
1568
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Exome Hom
Variant carriers
0
104
208
312
416
520
<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: 0.319 AC: 48444AN: 152072Hom.: 8223 Cov.: 32 AF XY: 0.321 AC XY: 23831AN XY: 74352 show subpopulations
GnomAD4 genome
AF:
AC:
48444
AN:
152072
Hom.:
Cov.:
32
AF XY:
AC XY:
23831
AN XY:
74352
show subpopulations
African (AFR)
AF:
AC:
9716
AN:
41506
American (AMR)
AF:
AC:
4203
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
AC:
973
AN:
3470
East Asian (EAS)
AF:
AC:
276
AN:
5182
South Asian (SAS)
AF:
AC:
1445
AN:
4816
European-Finnish (FIN)
AF:
AC:
4500
AN:
10548
Middle Eastern (MID)
AF:
AC:
104
AN:
294
European-Non Finnish (NFE)
AF:
AC:
26137
AN:
67956
Other (OTH)
AF:
AC:
693
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
1664
3328
4993
6657
8321
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Genome Het
Genome Hom
Variant carriers
0
488
976
1464
1952
2440
<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:
Hom.:
Bravo
AF:
Asia WGS
AF:
AC:
756
AN:
3478
ClinVar
Not reported inComputational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
DANN
Benign
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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