12-102886978-G-C

Position:

• chr12-102886978-G-C

Variant summary

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

The NM_000277.3(PAH):​c.352+7757C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 152,136 control chromosomes in the GnomAD database, including 2,525 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 0.17 (2525 hom., cov: 31)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0490

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.352+7757C>G		intron_variant		ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.352+7757C>G		intron_variant			NP_001341233.1
PAH	XM_017019370.2	c.352+7757C>G		intron_variant			XP_016874859.1
LOC124902999	XR_007063428.1	n.862+7045G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.352+7757C>G		intron_variant		1	NM_000277.3	ENSP00000448059.1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25686 AN: 152016 Hom.: 2518 Cov.: 31

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.0695

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.0865

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.167

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

GnomAD4 genome AF: 0.169 AC: 25701 AN: 152136 Hom.: 2525 Cov.: 31 AF XY: 0.168 AC XY: 12514 AN XY: 74360

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.327

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.0690

Gnomad4 SAS AF: 0.157

Gnomad4 FIN AF: 0.0865

Gnomad4 NFE AF: 0.144

Gnomad4 OTH AF: 0.164

Alfa AF: 0.0641 Hom.: 71

Bravo AF: 0.186

Asia WGS AF: 0.114 AC: 400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.66
DANN	Benign	0.62

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: rs1522305; hg19: chr12-103280756;