rs62508737

Positions:

• chr12-102843644-A-C
• chr12-102843644-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

This summary comes from the ClinGen Evidence Repository: The c.1199+2T>G variant in PAH occurs within the canonical splice donor of intron 11. It is predicted to cause skipping of biologically-relevant exon 11, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. This variant may be reported in the literature (PMID:25863075), but is unavailable for evaluation. Sequence analysis of a PKU mouse model with this variant revealed two cryptic splice donor sites, upstream and downstream of the wild-type splice site (PMID:11161825). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PVS1 LINK:https://erepo.genome.network/evrepo/ui/classification/CA386493122/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAH NM_000277.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 7.50

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 Likely_pathogenic. Variant got 10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.1199+2T>G		splice_donor_variant		ENST00000553106.6
PAH	NM_001354304.2	c.1199+2T>G		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.1199+2T>G		splice_donor_variant		1	NM_000277.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Mar 16, 2023	The c.1199+2T>G variant in PAH occurs within the canonical splice donor of intron 11. It is predicted to cause skipping of biologically-relevant exon 11, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss of function is an established disease mechanism. This variant may be reported in the literature (PMID: 25863075), but is unavailable for evaluation. Sequence analysis of a PKU mouse model with this variant revealed two cryptic splice donor sites, upstream and downstream of the wild-type splice site (PMID: 11161825). This variant is absent in population databases. In summary, this variant meets criteria to be classified as Likely Pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PM2, PVS1 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	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)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: -15
DS_DL_spliceai		0.64		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: rs62508737; hg19: chr12-103237422;