rs786200861

chr12-102843750-GAGA-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The NM_000277.3(PAH):c.1092_1094del(p.Leu365del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L364L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAH NM_000277.3 inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 1.86

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000277.3
• PM4: Nonframeshift variant in NON repetitive region in NM_000277.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 12-102843750-GAGA-G is Pathogenic according to our data. Variant chr12-102843750-GAGA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 597.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102843750-GAGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.1092_1094del	p.Leu365del	inframe_deletion	11/13	ENST00000553106.6
PAH	NM_001354304.2	c.1092_1094del	p.Leu365del	inframe_deletion	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.1092_1094del	p.Leu365del	inframe_deletion	11/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	May 04, 2019	The c.1092_1094delTCT variant in PAH has been previously reported as a single variant, found in trans with the Pathogenic variant (per internal PAH ClinGen Working Group classification, see ClinVar allele ID 15635) p.Gly272Ter in one proband with classic PKU (PMID: 1975559); phase was confirmed via parental testing (PM3). Apart from stating that the proband was identified via newborn screening further detail is provided regarding the proband's phenotype, including whether BH4 deficiency was formally excluded (PP4?). The variant is a protein-length changing variant in a non-repeat region (PM4). It is absent from control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1990	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences	Sep 19, 2023	- -

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs62516096; hg19: chr12-103237528;