Variant chr12-102851752-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PM1PM2PM5PP5_Very_StrongBP4

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

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:1

Conservation

PhyloP100: 0.787

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]

PAH links:

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ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.847A>G	p.Ile283Val	missense_variant	8/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	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 linkuse as main transcript	c.847A>G	p.Ile283Val	missense_variant	8/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

LINK: link

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

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.63

D;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.079

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.76

T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.41

T;T

MetaSVM

Pathogenic

0.79

MutationAssessor

Benign

-0.36

N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.65

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over