rs62508689

Positions:

• chr12-102844333-T-C
• chr12-102844333-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3 PP1 PP4 PP3 PM2

This summary comes from the ClinGen Evidence Repository: The c.1065+3A>G variant in PAH was detected in 2 siblings with an increased serum Phenylalanine level of 365 uM. BH4 deficiency was not assessed/reported. (PMID:8088845) They were compound heterozygous for Y414C. The c.1065+3A>G variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted for this variant in HSF and MaxEnt (Alteration of the WT donor site; activation of an intronic cryptic donor site). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP1, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA212751/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 splice_region, intron
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:2 O:1
• Conservation: PhyloP100: 0.172

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.
• PP1: 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.1065+3A>G		splice_region_variant, intron_variant		ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1065+3A>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.1065+3A>G		splice_region_variant, intron_variant		1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2015	- -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 14, 2018	- -

Phenylketonuria Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen PAH Variant Curation Expert Panel

Dec 10, 2018

The c.1065+3A>G variant in PAH was detected in 2 siblings with an increased serum Phenylalanine level of 365 uM. BH4 deficiency was not assessed/reported. (PMID: 8088845) They were compound heterozygous for Y414C. The c.1065+3A>G variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted for this variant in HSF and MaxEnt (Alteration of the WT donor site; activation of an intronic cryptic donor site). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP1, PP3, PP4. -

Hyperphenylalaninemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 1994

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.57		Position offset: 3

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

Publications

LitVar

Other links and lift over

dbSNP: rs62508689; hg19: chr12-103238111;