rs1037293795

Positions:

• chr12-102843698-G-A

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.1147C>T (p.Gln383Ter) variant in PAH is a nonsense variant predicted to undergo NMD, present in all biologically relevant transcripts, absent from all populations databases. It has been identified in a patient with classic PKU as homozygous, and in trans with a pathogenic variant (R408W), although defect in BH4 metabolism was not excluded in either patient. (PMID:24350308, 22763404). 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/CA16020949/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAH NM_000277.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 10.0

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]

PAH (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.1147C>T	p.Gln383*	stop_gained	11/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1147C>T	p.Gln383*	stop_gained	12/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1147C>T	p.Gln383*	stop_gained	11/13	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251242 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135764

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461412 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727026

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 24, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	This sequence change creates a premature translational stop signal (p.Gln383*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hyperphenylalaninemia and/or phenylketonuria (PMID: 22763404, 24350308, 29499199, 32668217). ClinVar contains an entry for this variant (Variation ID: 370701). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Dec 09, 2018	The c.1147C>T (p.Gln383Ter) variant in PAH is a nonsense variant predicted to undergo NMD, present in all biologically relevant transcripts, absent from all populations databases. It has been identified in a patient with classic PKU as homozygous, and in trans with a pathogenic variant (R408W), although defect in BH4 metabolism was not excluded in either patient. (PMID: 24350308, 22763404). 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	0.66
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.95
GERP RS		5.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1037293795; hg19: chr12-103237476;