12-102890194-A-G

Position:

• chr12-102890194-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000277.3(PAH):​c.352+4541T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.809 in 152,204 control chromosomes in the GnomAD database, including 50,478 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 0.81 (50478 hom., cov: 32)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.691

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.352+4541T>C		intron_variant		ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.352+4541T>C		intron_variant			NP_001341233.1
PAH	XM_017019370.2	c.352+4541T>C		intron_variant			XP_016874859.1
LOC124902999	XR_007063428.1	n.862+10261A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.352+4541T>C		intron_variant		1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.808 AC: 122954 AN: 152086 Hom.: 50421 Cov.: 32

Gnomad AFR AF: 0.933

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.820

Gnomad ASJ AF: 0.759

Gnomad EAS AF: 0.988

Gnomad SAS AF: 0.897

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.796

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

GnomAD4 genome AF: 0.809 AC: 123068 AN: 152204 Hom.: 50478 Cov.: 32 AF XY: 0.808 AC XY: 60123 AN XY: 74396

Gnomad4 AFR AF: 0.933

Gnomad4 AMR AF: 0.820

Gnomad4 ASJ AF: 0.759

Gnomad4 EAS AF: 0.988

Gnomad4 SAS AF: 0.898

Gnomad4 FIN AF: 0.677

Gnomad4 NFE AF: 0.734

Gnomad4 OTH AF: 0.795

Alfa AF: 0.751 Hom.: 47950

Bravo AF: 0.821

Asia WGS AF: 0.909 AC: 3161 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.75

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: rs10778209; hg19: chr12-103283972;