12-102851752-T-C

Position:

• chr12-102851752-T-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BP4

The ENST00000553106.6(PAH):​c.847A>G​(p.Ile283Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I283N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH ENST00000553106.6 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 0.787

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000553106.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-102851751-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 102877.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP5: Variant 12-102851752-T-C is Pathogenic according to our data. Variant chr12-102851752-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1065381.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.40779638). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.847A>G	p.Ile283Val	missense_variant	8/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.847A>G	p.Ile283Val	missense_variant	9/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.847A>G	p.Ile283Val	missense_variant	8/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen PAH Variant Curation Expert Panel

Dec 10, 2018

The c.847A>G (p.Ile283Val) variant in PAH is absent from all population databases, and is at the same amino acid as a previously established pathogenic variant (c.847A>T (p.Ile283Phe)). It has been identified in a patient with classic PKU (BH4 defect excluded), and in trans with a known pathogenic variant (c.1045T>C, p.Ser349Pro) PMID: 27121329. Summary evidence using PAH specific ACMG/AMP guidelines :PM2, PM5, PM3, PP4_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Uncertain	0.63	D;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.079
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.76	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.41	T;T
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Benign	-0.36	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.28	N;N
REVEL	Uncertain	0.44
Sift	Benign	0.44	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0020	B;.
Vest4		0.39
MutPred		0.63		Loss of catalytic residue at L288 (P = 0.0501);.;
MVP		0.89
MPC		0.028
ClinPred		0.47	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-103245530;