12-102851752-T-C

Variant names:

• chr12-102851752-T-C
• rs62517168
• NM_000277.3:c.847A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 15P and 1B. PM1 PM2 PM5 PP2 PP5_Very_Strong BP4

The NM_000277.3(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. 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. The gene PAH is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 0.787
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for PAH are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 39 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 chr12-102851751-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 102877.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 440 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: -0.64755 (below the threshold of 3.09). Trascript score misZ: -0.0084567 (below the threshold of 3.09). GenCC associations: The gene is linked to mild phenylketonuria, classic phenylketonuria, phenylketonuria, maternal phenylketonuria, mild hyperphenylalaninemia, tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria.
• 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.847A>G	p.Ile283Val	missense	Exon 8 of 13	NP_000268.1	P00439
	PAH	NM_001354304.2		c.847A>G	p.Ile283Val	missense	Exon 9 of 14	NP_001341233.1	P00439

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.847A>G	p.Ile283Val	missense	Exon 8 of 13	ENSP00000448059.1	P00439
	PAH	ENST00000906695.1		c.946A>G	p.Ile316Val	missense	Exon 9 of 14	ENSP00000576754.1
	PAH	ENST00000906692.1		c.847A>G	p.Ile283Val	missense	Exon 8 of 13	ENSP00000576751.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Phenylketonuria (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.079
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.41	T
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Benign	-0.36	N
PhyloP100		0.79
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.28	N
REVEL	Uncertain	0.44
Sift	Benign	0.44	T
Sift4G	Benign	0.58	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
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs62517168; hg19: chr12-103245530;