rs1801153

Positions:

• chr12-102838988-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000553106.6(PAH):​c.*187G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 617,870 control chromosomes in the GnomAD database, including 21,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9832 hom., cov: 33)
  • Exomes 𝑓: 0.20 (11802 hom.)
• Consequence: PAH ENST00000553106.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.611

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-102838988-C-T is Benign according to our data. Variant chr12-102838988-C-T is described in ClinVar as [Benign]. Clinvar id is 306911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAH	NM_000277.3	c.*187G>A		3_prime_UTR_variant	13/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.*187G>A		3_prime_UTR_variant	14/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.*187G>A		3_prime_UTR_variant	13/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000307000.7	c.*187G>A		3_prime_UTR_variant	14/14	5		ENSP00000303500

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47242 AN: 152030 Hom.: 9798 Cov.: 33

Gnomad AFR AF: 0.581

Gnomad AMI AF: 0.0888

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.00653

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.273

GnomAD4 exome AF: 0.202 AC: 94267 AN: 465722 Hom.: 11802 Cov.: 4 AF XY: 0.198 AC XY: 49060 AN XY: 247452

Gnomad4 AFR exome AF: 0.579

Gnomad4 AMR exome AF: 0.381

Gnomad4 ASJ exome AF: 0.198

Gnomad4 EAS exome AF: 0.00292

Gnomad4 SAS exome AF: 0.178

Gnomad4 FIN exome AF: 0.188

Gnomad4 NFE exome AF: 0.197

Gnomad4 OTH exome AF: 0.221

GnomAD4 genome AF: 0.311 AC: 47330 AN: 152148 Hom.: 9832 Cov.: 33 AF XY: 0.305 AC XY: 22719 AN XY: 74390

Gnomad4 AFR AF: 0.582

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.206

Gnomad4 EAS AF: 0.00655

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.270

Alfa AF: 0.225 Hom.: 6056

Bravo AF: 0.338

Asia WGS AF: 0.121 AC: 420 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2018	- -

Phenylketonuria Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.8
DANN	Benign	0.29

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: rs1801153; hg19: chr12-103232766;