14-54902596-G-A
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2
The NM_000161.3(GCH1):c.68C>T(p.Pro23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,500,604 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000161.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GCH1 | NM_000161.3 | c.68C>T | p.Pro23Leu | missense_variant | Exon 1 of 6 | ENST00000491895.7 | NP_000152.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00383 AC: 582AN: 152130Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.00426 AC: 429AN: 100738Hom.: 3 AF XY: 0.00403 AC XY: 227AN XY: 56270
GnomAD4 exome AF: 0.00513 AC: 6918AN: 1348362Hom.: 27 Cov.: 32 AF XY: 0.00500 AC XY: 3325AN XY: 664528
GnomAD4 genome AF: 0.00382 AC: 582AN: 152242Hom.: 1 Cov.: 33 AF XY: 0.00357 AC XY: 266AN XY: 74436
ClinVar
Submissions by phenotype
not provided Benign:7
GCH1: BS2 -
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This variant is associated with the following publications: (PMID: 31213404, 30314816, 25497597, 9328244, 19332422, 24993959) -
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GTP cyclohydrolase I deficiency;C1851920:Dystonia 5 Uncertain:1Benign:1
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GTP cyclohydrolase I deficiency Benign:2
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. -
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not specified Benign:1
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 individual with dystonia in trans with a nonsense variant (Jarman 1997). In a family with 2 members, it was identified in 2 affected individuals with DOPA-responsive dystonia and 1 with Parkinsons, this variant was identified in 1 individual with dystonia and 1 with Parkinsons (who also had a Phe104Leu variant) (Mencacci 2014). One of the family members with dystonia only had the Phe104Leu variant. This variant was described as benign due to its MAF. MAF 1.5% in Eur chr. -
GCH1-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Dystonia 5 Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at