rs841

Positions:

• chr14-54843774-G-A
• chr14-54843774-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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:8
• Conservation: PhyloP100: -1.63

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]

ACMG classification

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	Protein	UniProt
GCH1	NM_000161.3	c.*243C>T		3_prime_UTR_variant	6/6	ENST00000491895.7	NP_000152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7	c.*243C>T		3_prime_UTR_variant	6/6	1	NM_000161.3	ENSP00000419045	P1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33387 AN: 151942 Hom.: 3815 Cov.: 33

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

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.: 33 AF XY: 0.205 AC XY: 149338 AN XY: 726832

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.: 33 AF XY: 0.223 AC XY: 16559 AN XY: 74344

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 31, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 39. Only high quality variants are reported. -
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 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	- -

GTP cyclohydrolase I deficiency;C1851920:Dystonia 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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

Other links and lift over

dbSNP: rs841; hg19: chr14-55310492;