NM_000277.3:c.1316-1G>C

Variant names:

• chr12-102839219-C-G
• NM_000277.3:c.1316-1G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP4 PM3 PVS1_Strong

This summary comes from the ClinGen Evidence Repository: This variant c.1316-1G>C in PAH was detected in a patient with classic PKU with the pathogenic variant p.Arg243Gln (PMID:28982351). This variant was absent in population databases. This is a canonical variant in the -1 splice acceptor of intron 12; this would alter a region that is critical to protein function with nonsense mediated decay not predicted. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_Strong, PM2, PM3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386492906/MONDO:0009861/006

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAH NM_000277.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1
• Conservation: PhyloP100: 4.32

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.

• 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	c.1316-1G>C		splice_acceptor_variant, intron_variant	Intron 12 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.1316-1G>C		splice_acceptor_variant, intron_variant	Intron 13 of 13		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.1316-1G>C		splice_acceptor_variant, intron_variant	Intron 12 of 12	1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1

Dec 09, 2022

ClinGen PAH Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

This variant c.1316-1G>C in PAH was detected in a patient with classic PKU with the pathogenic variant p.Arg243Gln (PMID: 28982351). This variant was absent in population databases. This is a canonical variant in the -1 splice acceptor of intron 12; this would alter a region that is critical to protein function with nonsense mediated decay not predicted. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1_Strong, PM2, PM3, PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
GERP RS		4.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -23
DS_AL_spliceai		0.99		Position offset: -1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-103232997;