rs199475675

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_000277.3(PAH):​c.801G>T​(p.Gln267His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q267R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

14
4
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.25
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-102852857-T-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 12-102852856-C-A is Pathogenic according to our data. Variant chr12-102852856-C-A 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.801G>T p.Gln267His missense_variant 7/13 ENST00000553106.6 NP_000268.1 P00439A0A024RBG4
PAHNM_001354304.2 linkuse as main transcriptc.801G>T p.Gln267His missense_variant 8/14 NP_001341233.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PAHENST00000553106.6 linkuse as main transcriptc.801G>T p.Gln267His missense_variant 7/131 NM_000277.3 ENSP00000448059.1 P00439
PAHENST00000307000.7 linkuse as main transcriptc.786G>T p.Gln262His missense_variant 8/145 ENSP00000303500.2 J3KND8
PAHENST00000549247.6 linkuse as main transcriptn.560G>T non_coding_transcript_exon_variant 1/62
PAHENST00000635477.1 linkuse as main transcriptc.-40G>T upstream_gene_variant 5 ENSP00000489230.1 A0A0U1RQY4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251362
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135832
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461840
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
1.0
D;D
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.70
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.1
H;.
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-4.8
D;D
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.97
MutPred
0.93
Gain of sheet (P = 0.0827);.;
MVP
0.99
MPC
0.24
ClinPred
1.0
D
GERP RS
3.0
Varity_R
0.98
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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: rs199475675; hg19: chr12-103246634; COSMIC: COSV100187760; COSMIC: COSV100187760; API