rs1522296

chr12-102917009-G-Achr12-102917009-G-C

Variant summary

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

The NM_000277.3(PAH):c.60+62C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 1,451,900 control chromosomes in the GnomAD database, including 80,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11390 hom., cov: 33)
  • Exomes 𝑓: 0.32 (69576 hom.)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Benign reviewed by expert panel P:1 B:9
• Conservation: PhyloP100: -0.508

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=-0.84).
• BP6: Variant 12-102917009-G-A is Benign according to our data. Variant chr12-102917009-G-A is described in ClinVar as [Benign]. Clinvar id is 585207.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102917009-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.60+62C>T		intron_variant		ENST00000553106.6
PAH	NM_001354304.2	c.60+62C>T		intron_variant
PAH	XM_017019370.2	c.60+62C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.60+62C>T		intron_variant		1	NM_000277.3	P1

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56513 AN: 151900 Hom.: 11360 Cov.: 33

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.371

GnomAD4 exome AF: 0.320 AC: 416270 AN: 1299882 Hom.: 69576 AF XY: 0.318 AC XY: 208511 AN XY: 655128

Gnomad4 AFR exome AF: 0.506

Gnomad4 AMR exome AF: 0.525

Gnomad4 ASJ exome AF: 0.353

Gnomad4 EAS exome AF: 0.224

Gnomad4 SAS exome AF: 0.305

Gnomad4 FIN exome AF: 0.199

Gnomad4 NFE exome AF: 0.316

Gnomad4 OTH exome AF: 0.326

GnomAD4 genome AF: 0.372 AC: 56582 AN: 152018 Hom.: 11390 Cov.: 33 AF XY: 0.369 AC XY: 27407 AN XY: 74308

Gnomad4 AFR AF: 0.502

Gnomad4 AMR AF: 0.477

Gnomad4 ASJ AF: 0.371

Gnomad4 EAS AF: 0.221

Gnomad4 SAS AF: 0.316

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.315

Gnomad4 OTH AF: 0.367

Alfa AF: 0.232 Hom.: 678

Bravo AF: 0.400

Asia WGS AF: 0.296 AC: 1031 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:1 Benign:4

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	African/African American population allele frequency is 48.34% (rs1522296, 4299/8672 alleles, 1055 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.2.1, this variant is classified as BENIGN. Following criteria are met: BA1 -
Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_008690.2(NM_000277.2):c.60+62C>T in the gene PAH has an allele frequency of 0.496 in African subpopulation in the gnomAD database. A total of 2014 homozygous occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Nov 08, 2019	The c.60+62C>T intronic variant in PAH has a MAF of 0.3441 in gnomAD with 2,014 homozygotes.In summary, this variant meets criteria to be classified as benign for PAH. PAH-specific ACMG/AMP criteria applied: BA1, BS2, BP7. -
Likely pathogenic, no assertion criteria provided	case-control	Clinical Laboratory, Xuzhou Maternity and Child Health Care Hospital	Jun 26, 2018	- -

not specified Benign:3

Benign, criteria provided, single submitter	research	H3Africa Consortium	Oct 28, 2020	While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.521, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

PAH-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.98
Dann	Benign	0.43

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: rs1522296; hg19: chr12-103310787; COSMIC: COSV61015018; COSMIC: COSV61015018;