rs281865448

Positions:

• chr12-102866665-T-C
• chr12-102866665-T-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP4 PM3 PVS1 PM2

This summary comes from the ClinGen Evidence Repository: This c.442-2A>G variant in PAH was detected in a patient with PKU with the pathogenic variant c.441+3G>C (PMID:28982351). This variant was absent in population databases. This is a canonical variant in the -2 splice acceptor of intron 4. Exon skipping or use of a cryptic splice site would disrupt reading frame with nonsense mediated decay predicted. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386299735/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 5.31

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]

LOC124902999 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.442-2A>G		splice_acceptor_variant		ENST00000553106.6	NP_000268.1
LOC124902999	XR_007063428.1	n.807+1438T>C		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.442-2A>G		splice_acceptor_variant			NP_001341233.1
PAH	XM_017019370.2	c.442-2A>G		splice_acceptor_variant			XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.442-2A>G		splice_acceptor_variant		1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000549111.5	n.538-2A>G		splice_acceptor_variant, non_coding_transcript_variant		1
PAH	ENST00000307000.7	c.427-2A>G		splice_acceptor_variant		5		ENSP00000303500
PAH	ENST00000551988.5	n.530+10797A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen PAH Variant Curation Expert Panel

Dec 09, 2022

This c.442-2A>G variant in PAH was detected in a patient with PKU with the pathogenic variant c.441+3G>C (PMID: 28982351). This variant was absent in population databases. This is a canonical variant in the -2 splice acceptor of intron 4. Exon skipping or use of a cryptic splice site would disrupt reading frame with nonsense mediated decay predicted. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	D;D
GERP RS		6.1

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		0.25		Position offset: -12
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: rs281865448; hg19: chr12-103260443;