rs62514907

Positions:

• chr12-102866664-C-G
• chr12-102866664-C-T

Variant summary

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

The NM_000277.3(PAH):​c.442-1G>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: 32)
• Consequence: PAH NM_000277.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 5.24

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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.5, offset of 10, new splice context is: tttctcctacggttttaaAGatc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-102866664-C-G is Pathogenic according to our data. Variant chr12-102866664-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1065375.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102866664-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.442-1G>C		splice_acceptor_variant		ENST00000553106.6	NP_000268.1
LOC124902999	XR_007063428.1	n.807+1437C>G		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.442-1G>C		splice_acceptor_variant			NP_001341233.1
PAH	XM_017019370.2	c.442-1G>C		splice_acceptor_variant			XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.442-1G>C		splice_acceptor_variant		1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000549111.5	n.538-1G>C		splice_acceptor_variant, non_coding_transcript_variant		1
PAH	ENST00000307000.7	c.427-1G>C		splice_acceptor_variant		5		ENSP00000303500
PAH	ENST00000551988.5	n.530+10798G>C		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:2

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 29, 2024	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Dec 07, 2020	This c.442-1G>C variant in PAH was reported in trans with pathogenic variant p.Val388Met in 1 Han Chinese patient with PAH deficiency (PMID: 28982351). This variant is absent from population databases gnomAD, 1000 Genomes and ESP. This variant in the -1 splice acceptor site of intron 4 disrupts the reading frame and is predicted to undergo nonsense mediated decay (NMD). The exon is present in biologically-relevant transcripts. 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	0.38
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.97	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	0.94
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.45		Position offset: -11
DS_AL_spliceai		0.98		Position offset: -1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-103260442;