12-102844424-C-T

Position:

• chr12-102844424-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP4_Moderate PVS1 PM3

This summary comes from the ClinGen Evidence Repository: The c.977G>A (p.Trp326Ter) is a variant in PAH is a null variant (nonsense variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequencies in ethnically diverse control databases (gnomAD AF 0.00000399; PAH PM2 cutoff: <0.0002) (PM2). It has been identified in at least five PKU cases in whom BH4 deficiency was excluded (PP4_Moderate), in four cases in trans with known pathogenic variants (PM3_VeryStrong). It has been identified in at least two Chinese classic PKU cases (PMID:261600; PMID:1301927; PMID:28982351), in trans with the known pathogenic (per PAH VCEP) p.Y356X and p.R243Q variants; as a single heterozygous variant in a Chinese classic PKU case with BH4 deficiency excluded (PMID:24705691); in trans with the known pathogenic (per PAH VCEP) p.R261Q variant in one Slovak case with classic PKU with BH4 deficiency said to be excluded (PMID:23764561); one Chinese proband with mild hyperphenylalanemia in trans with c.1197A>T (p.V399V) (PMID:25456745). It is also listed Pathogenic in ClinVar by three labs (variant ID 579). Classification: PathogenicSupporting Criteria: PVS1, PM2; PM3_VeryStrong; PP4_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA229887/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PAH NM_000277.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5 O:1
• Conservation: PhyloP100: 6.06

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 14 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.977G>A	p.Trp326Ter	stop_gained	10/13	ENST00000553106.6
PAH	NM_001354304.2	c.977G>A	p.Trp326Ter	stop_gained	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.977G>A	p.Trp326Ter	stop_gained	10/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250724 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135478

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

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: 1458902 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 29, 2021	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 29499199). ClinVar contains an entry for this variant (Variation ID: 579). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp326*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 20, 2018	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Apr 13, 2020	The c.977G>A (p.Trp326Ter) is a variant in PAH is a null variant (nonsense variant) in a gene where LOF is a known mechanism of disease, leading to premature truncation and NMD (PVS1). It is present at extremely low frequencies in ethnically diverse control databases (gnomAD AF 0.00000399; PAH PM2 cutoff: <0.0002) (PM2). It has been identified in at least five PKU cases in whom BH4 deficiency was excluded (PP4_Moderate), in four cases in trans with known pathogenic variants (PM3_VeryStrong). It has been identified in at least two Chinese classic PKU cases (PMID: 261600; PMID: 1301927; PMID: 28982351), in trans with the known pathogenic (per PAH VCEP) p.Y356X and p.R243Q variants; as a single heterozygous variant in a Chinese classic PKU case with BH4 deficiency excluded (PMID: 24705691); in trans with the known pathogenic (per PAH VCEP) p.R261Q variant in one Slovak case with classic PKU with BH4 deficiency said to be excluded (PMID: 23764561); one Chinese proband with mild hyperphenylalanemia in trans with c.1197A>T (p.V399V) (PMID: 25456745). It is also listed Pathogenic in ClinVar by three labs (variant ID 579). Classification: Pathogenic Supporting Criteria: PVS1, PM2; PM3_VeryStrong; PP4_Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 22, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1989	- -

not provided Other:1

not provided, no classification provided

literature only

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A;A
Vest4		0.95
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 7

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

Publications

LitVar

Other links and lift over

dbSNP: rs62514959; hg19: chr12-103238202;