12-102839220-T-G

Position:

• chr12-102839220-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000553106.6(PAH):​c.1316-2A>C variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAH ENST00000553106.6 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 6.01

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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-102839220-T-G is Pathogenic according to our data. Variant chr12-102839220-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 932265.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102839220-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.1316-2A>C		splice_acceptor_variant		ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1316-2A>C		splice_acceptor_variant			NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1316-2A>C		splice_acceptor_variant		1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 18, 2022	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	May 14, 2020	Variant c.1316-2A>C in PAH was found in 1 Chinese patient with Phe levels >120 umol/L (PMID: 26322415). BH4 deficiency was excluded by analysis of urinary pterins and dihydropteridine reductase activity in erythrocytes (PP4-Moderate). Null variant, canonical -2 splice sites, is in a gene where LOF is a known mechanism of disease. Exon skipping disrupts the reading frame. Altered region is critical to protein function. Not predicted to undergo NMD, because coding exon number is 13 out of 13 coding exons (PVS1-Strong). Variant was found in trans with a pathogenic variant p.R241C (PMID: 26322415). All mutations identified in patients were confirmed by analyzing parental DNA via Sanger automated sequencing (PM3). Variant is absent from controls in gnomAD, PAGE, 1000 Genomes, or ESP (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1-Strong, PM2, PP4-Moderate, PM3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -24
DS_AL_spliceai		0.99		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs760830761; hg19: chr12-103232998;