rs2037639

Variant names:

• chr12-102877572-G-A
• rs2037639
• NM_000277.3:c.353-22C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102877572-G-A
• chr12-102877572-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1 BP7

This summary comes from the ClinGen Evidence Repository: 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 LINK:https://erepo.genome.network/evrepo/ui/classification/CA229520/MONDO:0009861/006

• 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:8 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 -9 ACMG points.

• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3	c.353-22C>T		intron_variant	Intron 3 of 12	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.353-22C>T		intron_variant	Intron 4 of 13		NP_001341233.1
PAH	XM_017019370.2	c.353-22C>T		intron_variant	Intron 3 of 6		XP_016874859.1
LOC124902999	XR_007063428.1	n.808-2307G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.353-22C>T		intron_variant	Intron 3 of 12	1	NM_000277.3	ENSP00000448059.1

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:8 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Benign:5

May 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2020

ClinGen PAH Variant Curation Expert Panel

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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 -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;