rs1722387

Positions:

• chr12-102847292-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000277.3(PAH):​c.913-341A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.863 in 358,714 control chromosomes in the GnomAD database, including 133,868 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.86 (55983 hom., cov: 32)
  • Exomes 𝑓: 0.87 (77885 hom.)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.710

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.913-341A>G		intron_variant		ENST00000553106.6
PAH	NM_001354304.2	c.913-341A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.913-341A>G		intron_variant		1	NM_000277.3	P1

Frequencies

GnomAD3 genomes AF: 0.857 AC: 130354 AN: 152086 Hom.: 55942 Cov.: 32

Gnomad AFR AF: 0.845

Gnomad AMI AF: 0.794

Gnomad AMR AF: 0.890

Gnomad ASJ AF: 0.826

Gnomad EAS AF: 0.850

Gnomad SAS AF: 0.916

Gnomad FIN AF: 0.907

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.849

Gnomad OTH AF: 0.857

GnomAD4 exome AF: 0.868 AC: 179163 AN: 206510 Hom.: 77885 Cov.: 0 AF XY: 0.873 AC XY: 96110 AN XY: 110118

Gnomad4 AFR exome AF: 0.845

Gnomad4 AMR exome AF: 0.898

Gnomad4 ASJ exome AF: 0.836

Gnomad4 EAS exome AF: 0.851

Gnomad4 SAS exome AF: 0.924

Gnomad4 FIN exome AF: 0.908

Gnomad4 NFE exome AF: 0.851

Gnomad4 OTH exome AF: 0.862

GnomAD4 genome AF: 0.857 AC: 130452 AN: 152204 Hom.: 55983 Cov.: 32 AF XY: 0.862 AC XY: 64133 AN XY: 74416

Gnomad4 AFR AF: 0.845

Gnomad4 AMR AF: 0.890

Gnomad4 ASJ AF: 0.826

Gnomad4 EAS AF: 0.850

Gnomad4 SAS AF: 0.915

Gnomad4 FIN AF: 0.907

Gnomad4 NFE AF: 0.849

Gnomad4 OTH AF: 0.858

Alfa AF: 0.845 Hom.: 52701

Bravo AF: 0.852

Asia WGS AF: 0.867 AC: 3019 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.0
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1722387; hg19: chr12-103241070;