12-102852811-T-C

Position:

• chr12-102852811-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3 PP3 PP4_Moderate PM2

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PP3: HSF: Broken WT Donor Site, New Donor Site. MaxEnt: Broken WT Donor Site.; PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP4_Moderate: IVS7+4A>G seen in 2 PKU patients. BH4 deficiency was ruled out. Upgraded per ClinGen PAH EP. (PMID:21147011); PM3: Detected in trans with A300S, pathogenic in ClinVar (PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PM2, PP4_Moderate, PM3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16020870/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PAH NM_000277.3 splice_region, intron
• Scores: Splicing: ADA: 0.9968
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 5.08

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.842+4A>G		splice_region_variant, intron_variant		ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.842+4A>G		splice_region_variant, intron_variant			NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.842+4A>G		splice_region_variant, intron_variant		1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.827+4A>G		splice_region_variant, intron_variant		5		ENSP00000303500.2
PAH	ENST00000635477.1	c.2+4A>G		splice_region_variant, intron_variant		5		ENSP00000489230.1
PAH	ENST00000549247.6	n.601+4A>G		splice_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461726 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:2

Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 12, 2018	PAH-specific ACMG/AMP criteria applied: PP3: HSF: Broken WT Donor Site, New Donor Site. MaxEnt: Broken WT Donor Site.; PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP4_Moderate: IVS7+4A>G seen in 2 PKU patients. BH4 deficiency was ruled out. Upgraded per ClinGen PAH EP. (PMID:21147011); PM3: Detected in trans with A300S, pathogenic in ClinVar (PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PM2, PP4_Moderate, PM3). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change falls in intron 7 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hyperphenylalaninemia (PMID: 21147011, 32668217). This variant is also known as IVS7+4A>G. ClinVar contains an entry for this variant (Variation ID: 439228). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 09, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25525159, 21147011, 35281663, 32668217) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Aug 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555204434; hg19: chr12-103246589;