14-54842787-G-A

Position:

• chr14-54842787-G-A

Variant summary

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

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.155

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=-0.6).
• 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	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	c.*1230C>T		3_prime_UTR_variant	6/6	1	NM_000161.3	P1

Frequencies

GnomAD3 genomes AF: 0.0730 AC: 11102 AN: 152038 Hom.: 646 Cov.: 32

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.: 0 AF XY: 0.0921 AC XY: 11352 AN XY: 123194

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.: 32 AF XY: 0.0741 AC XY: 5510 AN XY: 74374

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: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

Dystonia 5 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. -

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

Other links and lift over

dbSNP: rs56130647; hg19: chr14-55309505;