12-102912786-C-T

Position:

• chr12-102912786-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP4_Moderate PM2 PP3 PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.168+5G>A variant has been identified in at least 4 probands with phenotypes ranging from mild HPA to classic PKU, with at least 2 probands excluding BH4 deficiency (PMIDs: 9429153, 26413448, 27121329). It has been detected in the homozygous form (PMID:26413448) as well as in trans with pathogenic variants R297H (PMID:9429153), I65T, and S349P (PMID:27121329). 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 likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229453/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PAH NM_000277.3 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 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 Likely_pathogenic. Variant got 9 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.168+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000553106.6
PAH	NM_001354304.2	c.168+5G>A		splice_donor_5th_base_variant, intron_variant
PAH	XM_017019370.2	c.168+5G>A		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.168+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000277.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1437592 Hom.: 0 Cov.: 27 AF XY: 0.00000418 AC XY: 3 AN XY: 716932

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: 0.00000275

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	May 26, 2019	The c.168+5G>A variant has been identified in at least 4 probands with phenotypes ranging from mild HPA to classic PKU, with at least 2 probands excluding BH4 deficiency (PMIDs: 9429153, 26413448, 27121329). It has been detected in the homozygous form (PMID: 26413448) as well as in trans with pathogenic variants R297H (PMID: 9429153), I65T, and S349P (PMID: 27121329). 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 likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 26, 2023	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. ClinVar contains an entry for this variant (Variation ID: 102605). This variant is also known as IVS2+5G>A. This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 9429153, 29288420, 33465300). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.168+5G nucleotide in the PAH gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8364593, 21890392, 22330942, 22526846). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. -

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	-0.47
CADD	Benign	0.44
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.91		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;