12-102852922-C-T

Position:

chr12-102852922-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2BP4BA1

This summary comes from the ClinGen Evidence Repository: The c.735G>A (p.Val245=) variant in PAH has a MAF of 0.29058 in ExAC (BA1; http://exac.broadinstitute.org) with 6,524 homozygotes (BS2). This is a synonymous variant, predicted tolerated and benign in SIFT, Polyphen. MutationTaster predicted polymorphism with no abrogation of splice sites (BP4). In summary, this variant meets criteria to be classified as benign. LINK:https://erepo.genome.network/evrepo/ui/classification/CA145982/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.21 ( 4861 hom., cov: 32)

Exomes 𝑓: 0.26 ( 56669 hom. )

Consequence

PAH
NM_000277.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:15O:1

Conservation

PhyloP100: -0.253

Variant links:

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 links:

PAH (HGNC:):

PAH links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS2

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/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.735G>A	p.Val245Val	synonymous_variant	7/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.735G>A	p.Val245Val	synonymous_variant	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.735G>A	p.Val245Val	synonymous_variant	7/13	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000307000.7 linkuse as main transcript	c.720G>A	p.Val240Val	synonymous_variant	8/14	5		ENSP00000303500.2	J3KND8
PAH	ENST00000549247.6 linkuse as main transcript	n.494G>A		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes

AF:

0.212

AC:

32231

AN:

151912

Hom.:

4861

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0493

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.194

Gnomad ASJ

AF:

0.284

Gnomad EAS

AF:

0.750

Gnomad SAS

AF:

0.374

Gnomad FIN

AF:

0.296

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.245

Gnomad OTH

AF:

0.230

GnomAD3 exomes

AF:

0.291

AC:

72975

AN:

251140

Hom.:

13482

AF XY:

0.297

AC XY:

40347

AN XY:

135708

show subpopulations

Gnomad AFR exome

AF:

0.0423

Gnomad AMR exome

AF:

0.210

Gnomad ASJ exome

AF:

0.284

Gnomad EAS exome

AF:

0.753

Gnomad SAS exome

AF:

0.373

Gnomad FIN exome

AF:

0.305

Gnomad NFE exome

AF:

0.252

Gnomad OTH exome

AF:

0.282

GnomAD4 exome

AF:

0.260

AC:

379698

AN:

1461694

Hom.:

56669

Cov.:

AF XY:

0.264

AC XY:

192222

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.0385

Gnomad4 AMR exome

AF:

0.205

Gnomad4 ASJ exome

AF:

0.289

Gnomad4 EAS exome

AF:

0.759

Gnomad4 SAS exome

AF:

0.369

Gnomad4 FIN exome

AF:

0.308

Gnomad4 NFE exome

AF:

0.238

Gnomad4 OTH exome

AF:

0.273

GnomAD4 genome

AF:

0.212

AC:

32232

AN:

152030

Hom.:

4861

Cov.:

AF XY:

0.218

AC XY:

16165

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0493

Gnomad4 AMR

AF:

0.194

Gnomad4 ASJ

AF:

0.284

Gnomad4 EAS

AF:

0.750

Gnomad4 SAS

AF:

0.372

Gnomad4 FIN

AF:

0.296

Gnomad4 NFE

AF:

0.245

Gnomad4 OTH

AF:

0.232

Alfa

AF:

0.235

Hom.:

5927

Bravo

AF:

0.198

Asia WGS

AF:

0.465

AC:

1616

AN:

3478

EpiCase

AF:

0.247

EpiControl

AF:

0.248

ClinVar

Significance: Benign

Submissions summary: Benign:15Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Benign:9

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 19, 2021	- -
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	Apr 24, 2018	The c.735G>A (p.Val245=) variant in PAH has a MAF of 0.29058 in ExAC (BA1; http://exac.broadinstitute.org) with 6,524 homozygotes (BS2). This is a synonymous variant, predicted tolerated and benign in SIFT, Polyphen. MutationTaster predicted polymorphism with no abrogation of splice sites (BP4). In summary, this variant meets criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:3Other: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	This variant is associated with the following publications: (PMID: 29390883, 32668217) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2016	Variant summary: The variant of interest causes a synonymous change involving a non-conserved nucleotide with 3/5 Alamut algorithms predicting the creation of a splice donor site. However, these in silico predictions have not been confirmed with functional studies. This variant was found in 35308/121456 control chromosomes (6524 homozygotes) at a frequency of 0.2907061, which exceeds the predicted the maximal expected frequency of a pathogenic PAH allele (0.0079057), highly suggesting this variant is benign. In addition, a reputable clinical laboratory classifies the variant as Benign. The variant of interest is cited as a known common polymorphism in the literature. Taken together, this variant was classified as a Benign variant. -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2018	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Benign

7.8

DANN

Benign

0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over