rs199475568

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_000277.3(PAH):ā€‹c.187A>Gā€‹(p.Thr63Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,118 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T63P) has been classified as Pathogenic.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)

Consequence

PAH
NM_000277.3 missense

Scores

6
7
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.13
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a strand (size 7) in uniprot entity PH4H_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000277.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-102894900-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PAHNM_000277.3 linkuse as main transcriptc.187A>G p.Thr63Ala missense_variant 3/13 ENST00000553106.6 NP_000268.1 P00439A0A024RBG4
PAHNM_001354304.2 linkuse as main transcriptc.187A>G p.Thr63Ala missense_variant 4/14 NP_001341233.1
PAHXM_017019370.2 linkuse as main transcriptc.187A>G p.Thr63Ala missense_variant 3/7 XP_016874859.1
LOC124902999XR_007063428.1 linkuse as main transcriptn.863-9798T>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PAHENST00000553106.6 linkuse as main transcriptc.187A>G p.Thr63Ala missense_variant 3/131 NM_000277.3 ENSP00000448059.1 P00439

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152118
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
30
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152118
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74322
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.49
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.88
D;D;D;D
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.92
D;D;D;D
M_CAP
Benign
0.071
D
MetaRNN
Uncertain
0.66
D;D;D;D
MetaSVM
Pathogenic
1.2
D
MutationAssessor
Pathogenic
3.1
M;.;.;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-2.0
N;N;N;N
REVEL
Uncertain
0.59
Sift
Benign
0.63
T;T;T;D
Sift4G
Benign
0.78
T;T;T;.
Polyphen
0.28
B;.;.;.
Vest4
0.82
MutPred
0.36
Loss of phosphorylation at T63 (P = 0.1459);.;Loss of phosphorylation at T63 (P = 0.1459);Loss of phosphorylation at T63 (P = 0.1459);
MVP
0.92
MPC
0.031
ClinPred
0.98
D
GERP RS
6.2
Varity_R
0.60
gMVP
0.77

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199475568; hg19: chr12-103288678; API