Variant 14-54842787-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_000161.3(GCH1):c.*1230C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.084 in 394,304 control chromosomes in the GnomAD database, including 1,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.073 ( 646 hom., cov: 32)

Exomes 𝑓: 0.091 ( 1292 hom. )

Consequence

GCH1
NM_000161.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.155

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=-0.6).

BP6

Variant 14-54842787-G-A is Benign according to our data. Variant chr14-54842787-G-A is described in ClinVar as [Benign]. Clinvar id is 313367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.107 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.*1230C>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.*1230C>T		3_prime_UTR_variant	6/6	1	NM_000161.3	P1	P30793-1

Frequencies

GnomAD3 genomes

AF:

0.0730

AC:

11102

AN:

152038

Hom.:

646

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.153

Gnomad AMR

AF:

0.0501

Gnomad ASJ

AF:

0.0418

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0186

Gnomad FIN

AF:

0.166

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.0607

GnomAD4 exome

AF:

0.0910

AC:

22035

AN:

242148

Hom.:

1292

Cov.:

AF XY:

0.0921

AC XY:

11352

AN XY:

123194

show subpopulations

Gnomad4 AFR exome

AF:

0.0154

Gnomad4 AMR exome

AF:

0.0448

Gnomad4 ASJ exome

AF:

0.0410

Gnomad4 EAS exome

AF:

0.0000456

Gnomad4 SAS exome

AF:

0.0219

Gnomad4 FIN exome

AF:

0.149

Gnomad4 NFE exome

AF:

0.109

Gnomad4 OTH exome

AF:

0.0767

GnomAD4 genome

AF:

0.0730

AC:

11101

AN:

152156

Hom.:

646

Cov.:

AF XY:

0.0741

AC XY:

5510

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0163

Gnomad4 AMR

AF:

0.0500

Gnomad4 ASJ

AF:

0.0418

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0187

Gnomad4 FIN

AF:

0.166

Gnomad4 NFE

AF:

0.109

Gnomad4 OTH

AF:

0.0601

Alfa

AF:

0.0741

Hom.:

128

Bravo

AF:

0.0602

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GTP cyclohydrolase I deficiency

Benign:1

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2018

- -

Dystonia 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

Cadd

Benign

7.8

Dann

Benign

0.80

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

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