NM_000277.3:c.353-22C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124902999 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	NM_000277.3	MANE Select	c.353-22C>T		intron	N/A	NP_000268.1
	PAH	NM_001354304.2		c.353-22C>T		intron	N/A	NP_001341233.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAH	ENST00000553106.6	TSL:1 MANE Select	c.353-22C>T		intron	N/A	ENSP00000448059.1
	PAH	ENST00000549111.5	TSL:1	n.449-22C>T		intron	N/A
	PAH	ENST00000307000.7	TSL:5	c.338-22C>T		intron	N/A	ENSP00000303500.2

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

GnomAD2 exomes AF: 0.274 AC: 68767 AN: 250962 AF XY: 0.278

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 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

African (AFR) AF: 0.120 AC: 3930 AN: 32788

American (AMR) AF: 0.189 AC: 8437 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7244 AN: 25908

East Asian (EAS) AF: 0.680 AC: 26906 AN: 39540

South Asian (SAS) AF: 0.329 AC: 28180 AN: 85578

European-Finnish (FIN) AF: 0.266 AC: 14203 AN: 53348

Middle Eastern (MID) AF: 0.273 AC: 1556 AN: 5706

European-Non Finnish (NFE) AF: 0.228 AC: 246332 AN: 1079078

Other (OTH) AF: 0.261 AC: 15434 AN: 59196

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

African (AFR) AF: 0.129 AC: 5350 AN: 41518

American (AMR) AF: 0.190 AC: 2907 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 962 AN: 3470

East Asian (EAS) AF: 0.690 AC: 3556 AN: 5150

South Asian (SAS) AF: 0.333 AC: 1603 AN: 4812

European-Finnish (FIN) AF: 0.259 AC: 2740 AN: 10566

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15615 AN: 67978

Other (OTH) AF: 0.234 AC: 492 AN: 2104

Alfa AF: 0.214 Hom.: 5372

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 01, 2021

Pars Genome Lab

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

not provided Benign:2 Other:1

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

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.1
DANN	Benign	0.60
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2037639; hg19: chr12-103271350;