12-102912791-C-T

Position:

• chr12-102912791-C-T

Variant summary

Our verdict is Uncertain significance. Variant got -2 ACMG points: 3P and 5B. PM2 BS2 PP3 BP2

This summary comes from the ClinGen Evidence Repository: The c.168G>A (p.Glu56=) variant in PAH has been reported as a polymoprhism. It was found in Arab patients’ DNA, including patients and controls (zygosity not reported). (BS2; PMID:18299955) However, this variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). While it is a synonymous variant, alteration of the WT donor site affecting splicing is suggested by Human Splicing Finder and Alamut (PP3). It was observed in cis with a pathogenic variant, IVS2+1G>A (BP2; PMID:24368688). In summary, this variant meets criteria to be classified as uncertain significance for PAH due to conflicting evidence. ACMG/AMP criteria applied: BS2, BP2, PM2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA229457/MONDO:0009861/006

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAH NM_000277.3 splice_region, synonymous
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance reviewed by expert panel U:2 B:1 O:1
• Conservation: PhyloP100: 2.59

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 -2 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.168G>A	p.Glu56=	splice_region_variant, synonymous_variant	2/13	ENST00000553106.6
PAH	NM_001354304.2	c.168G>A	p.Glu56=	splice_region_variant, synonymous_variant	3/14
PAH	XM_017019370.2	c.168G>A	p.Glu56=	splice_region_variant, synonymous_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.168G>A	p.Glu56=	splice_region_variant, synonymous_variant	2/13	1	NM_000277.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449126 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 721946

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 14, 2022	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Nov 10, 2019	The c.168G>A (p.Glu56=) variant in PAH has been reported as a polymoprhism. It was found in Arab patients' DNA, including patients and controls (zygosity not reported). (BS2; PMID: 18299955) However, this variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). While it is a synonymous variant, alteration of the WT donor site affecting splicing is suggested by Human Splicing Finder and Alamut (PP3). It was observed in cis with a pathogenic variant, IVS2+1G>A (BP2; PMID: 24368688). In summary, this variant meets criteria to be classified as uncertain significance for PAH due to conflicting evidence. ACMG/AMP criteria applied: BS2, BP2, PM2, PP3. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

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	-0.31
CADD	Benign	21
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs199475567; hg19: chr12-103306569;