chr12-102852811-T-A

Position:

• chr12-102852811-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000277.3(PAH):​c.842+4A>T variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAH NM_000277.3 splice_region, intron
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 5.08

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.842+4A>T		splice_region_variant, intron_variant		ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.842+4A>T		splice_region_variant, intron_variant			NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.842+4A>T		splice_region_variant, intron_variant		1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.827+4A>T		splice_region_variant, intron_variant		5		ENSP00000303500.2
PAH	ENST00000635477.1	c.2+4A>T		splice_region_variant, intron_variant		5		ENSP00000489230.1
PAH	ENST00000549247.6	n.601+4A>T		splice_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen PAH Variant Curation Expert Panel

Jun 09, 2019

The c.842+4A>T PAH variant has been reported in PKU patients (PMID: 25863075). This variant is absent from 1000G, ESP, and gnomAD databases. This is an intronic variant in a highly conserved nucleotide, and computational analyses predict that this variant abolishes the donor splice site of intron 7. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555204434; hg19: chr12-103246589;