rs2037639

chr12-102877572-G-Achr12-102877572-G-T

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.353-22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 1,577,894 control chromosomes in the GnomAD database, including 53,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4517 hom., cov: 31)
  • Exomes 𝑓: 0.25 (48672 hom.)
• Consequence: PAH NM_000277.3 intron
• Clinical Significance: Benign reviewed by expert panel B:7 O:1
• Conservation: PhyloP100: -0.216

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]

LOC124902999 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-102877572-G-A is Benign according to our data. Variant chr12-102877572-G-A is described in ClinVar as [Benign]. Clinvar id is 102654.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102877572-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3	c.353-22C>T		intron_variant		ENST00000553106.6
LOC124902999	XR_007063428.1	n.808-2307G>A		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2	c.353-22C>T		intron_variant
PAH	XM_017019370.2	c.353-22C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAH	ENST00000553106.6	c.353-22C>T		intron_variant		1	NM_000277.3	P1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33548 AN: 151976 Hom.: 4519 Cov.: 31

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.233

GnomAD3 exomes AF: 0.274 AC: 68767 AN: 250962 Hom.: 11705 AF XY: 0.278 AC XY: 37735 AN XY: 135654

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.191

Gnomad ASJ exome AF: 0.274

Gnomad EAS exome AF: 0.707

Gnomad SAS exome AF: 0.333

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.263

GnomAD4 exome AF: 0.247 AC: 352222 AN: 1425802 Hom.: 48672 Cov.: 26 AF XY: 0.250 AC XY: 178113 AN XY: 711592

Gnomad4 AFR exome AF: 0.120

Gnomad4 AMR exome AF: 0.189

Gnomad4 ASJ exome AF: 0.280

Gnomad4 EAS exome AF: 0.680

Gnomad4 SAS exome AF: 0.329

Gnomad4 FIN exome AF: 0.266

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.221 AC: 33549 AN: 152092 Hom.: 4517 Cov.: 31 AF XY: 0.224 AC XY: 16679 AN XY: 74346

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.190

Gnomad4 ASJ AF: 0.277

Gnomad4 EAS AF: 0.690

Gnomad4 SAS AF: 0.333

Gnomad4 FIN AF: 0.259

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.234

Alfa AF: 0.217 Hom.: 4312

Bravo AF: 0.214

Asia WGS AF: 0.432 AC: 1504 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 13, 2023	- -
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	Mar 27, 2020	The c.353-22C>T variant in PAH has a MAF of 0.7066 in the gnomAD East Asian population. This intronic variant does not have a predicted impact on splicing. In summary this variant meets criteria to be classified as benign. PAH-specific ACMG/AMP criteria applied: BA1, BP7 -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:1 Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	4.1
Dann	Benign	0.60

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: rs2037639; hg19: chr12-103271350;