rs62507288

Positions:

• chr12-102912786-C-A
• chr12-102912786-C-G
• chr12-102912786-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3 PM2 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.168+5G>T variant has been identified in at least 2 probands, with at least 1 classic PKU proband excluding BH4 deficiency (PMIDs: 30747360). This variant is absent from 1000G, ESP, and gnomAD databases. Computational analysis predicts an alteration of the WT donor site, most probably affecting splicing. In summary, this variant meets criteria to be classified as unknown significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229455/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 splice_region, intron
• Scores: Splicing: ADA: 0.9923
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 O:1
• Conservation: PhyloP100: -0.0810

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: 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.168+5G>T		splice_region_variant, intron_variant		ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.168+5G>T		splice_region_variant, intron_variant			NP_001341233.1
PAH	XM_017019370.2	c.168+5G>T		splice_region_variant, intron_variant			XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.168+5G>T		splice_region_variant, intron_variant		1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen PAH Variant Curation Expert Panel

Aug 25, 2019

The c.168+5G>T variant has been identified in at least 2 probands, with at least 1 classic PKU proband excluding BH4 deficiency (PMIDs: 30747360). This variant is absent from 1000G, ESP, and gnomAD databases. Computational analysis predicts an alteration of the WT donor site, most probably affecting splicing. In summary, this variant meets criteria to be classified as unknown significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PP3. -

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_noAF	Benign	-0.45
CADD	Benign	0.35
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.92		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs62507288; hg19: chr12-103306564;