14-54861917-C-T

Position:

• chr14-54861917-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000161.3(GCH1):​c.454-2181G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 151,900 control chromosomes in the GnomAD database, including 9,199 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (9199 hom., cov: 31)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.262

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCH1	NM_000161.3	c.454-2181G>A		intron_variant		ENST00000491895.7	NP_000152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7	c.454-2181G>A		intron_variant		1	NM_000161.3	ENSP00000419045.2

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51690 AN: 151782 Hom.: 9186 Cov.: 31

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.459

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.311

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.341 AC: 51760 AN: 151900 Hom.: 9199 Cov.: 31 AF XY: 0.343 AC XY: 25453 AN XY: 74224

Gnomad4 AFR AF: 0.392

Gnomad4 AMR AF: 0.367

Gnomad4 ASJ AF: 0.188

Gnomad4 EAS AF: 0.363

Gnomad4 SAS AF: 0.156

Gnomad4 FIN AF: 0.413

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.308

Alfa AF: 0.323 Hom.: 2008

Bravo AF: 0.341

Asia WGS AF: 0.236 AC: 820 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.2
DANN	Benign	0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs9671371; hg19: chr14-55328635;