12-102852816-G-C

Position:

• chr12-102852816-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000277.3(PAH):​c.841C>G​(p.Pro281Ala) variant causes a missense, splice region 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. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P281L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 missense, splice_region
• Scores: Splicing: ADA: 0.9841
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

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 chr12-102852815-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 12-102852816-G-C is Pathogenic according to our data. Variant chr12-102852816-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 120289.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-102852816-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.841C>G	p.Pro281Ala	missense_variant, splice_region_variant	7/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.841C>G	p.Pro281Ala	missense_variant, splice_region_variant	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.841C>G	p.Pro281Ala	missense_variant, splice_region_variant	7/13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.826C>G	p.Pro276Ala	missense_variant, splice_region_variant	8/14	5		ENSP00000303500.2
PAH	ENST00000635477.1	c.1C>G	p.Pro1Ala	missense_variant, splice_region_variant	1/6	5		ENSP00000489230.1
PAH	ENST00000549247.6	n.600C>G		splice_region_variant, non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Phenylketonuria Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Inserm U 954, Faculté de Médecine de Nancy

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.9	H;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.7	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.91
MutPred		0.97		Loss of glycosylation at T278 (P = 0.0693);.;
MVP		1.0
MPC		0.24
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.91
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

Other links and lift over

dbSNP: rs199475654; hg19: chr12-103246594;