dbSNP rs62514955: PAH:c.842+2T>A (chr12-102852813-A-T) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PP4_ModeratePM2PVS1PM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.842+2T>A variant in PAH is a splice-site variant predicted to result in skipping of exon 8, leading to a frameshift, premature protein truncation, and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is reported Pathogenic in Clinvar (ID 614). It has been reported among multiple patients with classic PKU, with BH4 deficiency formally excluded (PMID:17557229; PMID:21307867) (PP4_Moderate) and has been reported in trans with multiple Pathogenic and Likely Pathogenic mutations, including R111X (P, ClinGen); P281L (P, ClinGen); R413P (P, ClinGen); R243Q (P, ClinGen); R261Q (LP/P, ClinGen); R400T (unknown, ClinGen) (PMID:17557229) (PM3_Strong).Classification: PathogenicSupporting Criteria: PVS1, PM2, PM3_Strong, PP4_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA229813/MONDO:0009861/006

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PAH
NM_000277.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:5O:1

Conservation

PhyloP100: 9.32

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM3

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 rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.842+2T>A		splice_donor_variant, intron_variant	Intron 7 of 12	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.842+2T>A		splice_donor_variant, intron_variant	Intron 8 of 13		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 link	c.842+2T>A	splice_donor_variant, intron_variant	Intron 7 of 12	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000307000.7 link	c.827+2T>A	splice_donor_variant, intron_variant	Intron 8 of 13	5		ENSP00000303500.2	J3KND8
PAH	ENST00000635477.1 link	c.2+2T>A	splice_donor_variant, intron_variant	Intron 1 of 5	5		ENSP00000489230.1	A0A0U1RQY4
PAH	ENST00000549247.6 link	n.601+2T>A	splice_donor_variant, intron_variant	Intron 1 of 5	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461720

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727172

show subpopulations

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:5

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PM3_VeryStrong+PP4 -

Jan 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 7 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with phenylketonuria (PMID: 26322415, 27264808). This variant is also known as IVS7+2T>A. ClinVar contains an entry for this variant (Variation ID: 614). 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. -

Apr 16, 2020

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.842+2T>A variant in PAH is a splice-site variant predicted to result in skipping of exon 8, leading to a frameshift, premature protein truncation, and NMD (PVS1). It is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). It is reported Pathogenic in Clinvar (ID 614). It has been reported among multiple patients with classic PKU, with BH4 deficiency formally excluded (PMID: 17557229; PMID: 21307867) (PP4_Moderate) and has been reported in trans with multiple Pathogenic and Likely Pathogenic mutations, including R111X (P, ClinGen); P281L (P, ClinGen); R413P (P, ClinGen); R243Q (P, ClinGen); R261Q (LP/P, ClinGen); R400T (unknown, ClinGen) (PMID: 17557229) (PM3_Strong). Classification: Pathogenic Supporting Criteria: PVS1, PM2, PM3_Strong, PP4_Moderate -

Nov 01, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 09, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Other:1

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

GERP RS

5.7

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

0.93

SpliceAI score (max)

0.94

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.94

Position offset: 2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over