12-102840507-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000277.3(PAH):​c.1208C>G​(p.Ala403Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. A403V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PAH
NM_000277.3 missense

Scores

8
10
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.70
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 8 ACMG points.

PM1
In a helix (size 11) in uniprot entity PH4H_HUMAN there are 16 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 chr12-102840507-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAHNM_000277.3 linkc.1208C>G p.Ala403Gly missense_variant Exon 12 of 13 ENST00000553106.6 NP_000268.1 P00439A0A024RBG4
PAHNM_001354304.2 linkc.1208C>G p.Ala403Gly missense_variant Exon 13 of 14 NP_001341233.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAHENST00000553106.6 linkc.1208C>G p.Ala403Gly missense_variant Exon 12 of 13 1 NM_000277.3 ENSP00000448059.1 P00439

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Pathogenic
0.35
D
BayesDel_noAF
Pathogenic
0.26
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D;D
Eigen
Uncertain
0.44
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.92
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.8
M;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-3.0
D;D
REVEL
Pathogenic
0.80
Sift
Uncertain
0.011
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.085
B;.
Vest4
0.70
MutPred
0.76
Loss of stability (P = 0.0921);.;
MVP
0.98
MPC
0.12
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.88
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-103234285; API