rs841

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000543643.6(GCH1):c.*12+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,613,118 control chromosomes in the GnomAD database, including 37,505 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 3819 hom., cov: 33)

Exomes 𝑓: 0.21 ( 33686 hom. )

Consequence

GCH1
ENST00000543643.6 splice_region, intron

Scores

Splicing: ADA: 0.00001206

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.63

Variant links:

Genes affected

GCH1 (HGNC:4193): (GTP cyclohydrolase 1) This gene encodes a member of the GTP cyclohydrolase family. The encoded protein is the first and rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis, catalyzing the conversion of GTP into 7,8-dihydroneopterin triphosphate. BH4 is an essential cofactor required by aromatic amino acid hydroxylases as well as nitric oxide synthases. Mutations in this gene are associated with malignant hyperphenylalaninemia and dopa-responsive dystonia. Several alternatively spliced transcript variants encoding different isoforms have been described; however, not all variants give rise to a functional enzyme. [provided by RefSeq, Jul 2008]

GCH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 14-54843774-G-A is Benign according to our data. Variant chr14-54843774-G-A is described in ClinVar as [Benign]. Clinvar id is 313386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-54843774-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCH1	NM_000161.3 linkuse as main transcript	c.*243C>T		3_prime_UTR_variant	6/6	ENST00000491895.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCH1	ENST00000491895.7 linkuse as main transcript	c.*243C>T		3_prime_UTR_variant	6/6	1	NM_000161.3	P1	P30793-1

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33387

AN:

151942

Hom.:

3815

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.307

Gnomad AMR

AF:

0.295

Gnomad ASJ

AF:

0.146

Gnomad EAS

AF:

0.354

Gnomad SAS

AF:

0.131

Gnomad FIN

AF:

0.246

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.203

Gnomad OTH

AF:

0.219

GnomAD3 exomes

AF:

0.219

AC:

54642

AN:

250038

Hom.:

6668

AF XY:

0.209

AC XY:

28362

AN XY:

135620

show subpopulations

Gnomad AFR exome

AF:

0.206

Gnomad AMR exome

AF:

0.308

Gnomad ASJ exome

AF:

0.146

Gnomad EAS exome

AF:

0.359

Gnomad SAS exome

AF:

0.124

Gnomad FIN exome

AF:

0.245

Gnomad NFE exome

AF:

0.198

Gnomad OTH exome

AF:

0.205

GnomAD4 exome

AF:

0.210

AC:

306321

AN:

1461058

Hom.:

33686

Cov.:

AF XY:

0.205

AC XY:

149338

AN XY:

726832

show subpopulations

Gnomad4 AFR exome

AF:

0.209

Gnomad4 AMR exome

AF:

0.307

Gnomad4 ASJ exome

AF:

0.147

Gnomad4 EAS exome

AF:

0.387

Gnomad4 SAS exome

AF:

0.130

Gnomad4 FIN exome

AF:

0.245

Gnomad4 NFE exome

AF:

0.206

Gnomad4 OTH exome

AF:

0.204

GnomAD4 genome

AF:

0.220

AC:

33426

AN:

152060

Hom.:

3819

Cov.:

AF XY:

0.223

AC XY:

16559

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.212

Gnomad4 AMR

AF:

0.295

Gnomad4 ASJ

AF:

0.146

Gnomad4 EAS

AF:

0.355

Gnomad4 SAS

AF:

0.132

Gnomad4 FIN

AF:

0.246

Gnomad4 NFE

AF:

0.203

Gnomad4 OTH

AF:

0.217

Alfa

AF:

0.202

Hom.:

3527

Bravo

AF:

0.226

Asia WGS

AF:

0.202

AC:

703

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GTP cyclohydrolase I deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Genome-Nilou Lab	Aug 10, 2021	- -

Dystonia 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Genome-Nilou Lab	Aug 10, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

GTP cyclohydrolase I deficiency;C1851920:Dystonia 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

Cadd

Benign

0.30

Dann

Benign

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000012

dbscSNV1_RF

Benign

0.0080

SpliceAI score (max)

0.12

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