rs1555209575

chr12-102912832-C-A

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.127G>T(p.Glu43Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 5.03

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: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-102912832-C-A is Pathogenic according to our data. Variant chr12-102912832-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 557124.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102912832-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.127G>T	p.Glu43Ter	stop_gained	2/13	ENST00000553106.6
PAH	NM_001354304.2	c.127G>T	p.Glu43Ter	stop_gained	3/14
PAH	XM_017019370.2	c.127G>T	p.Glu43Ter	stop_gained	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.127G>T	p.Glu43Ter	stop_gained	2/13	1	NM_000277.3	P1

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, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Apr 03, 2019	The c.127G>T (p.Glu43*) variant is a nonsense variant in exon 2 of 13 in PAH, predicted to undergo nonsense mediated decay with the truncated region critical to protein function. It has been reported in 2 individuals with PKU (BH4 deficiency not excluded). (PP4; PMID: 26503515). This variant is absent from population databases (PM2). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1555209575; hg19: chr12-103306610;