chr14-54849552-A-G

Position:

• chr14-54849552-A-G

Variant summary

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

The NM_000161.3(GCH1):​c.510-2422T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 151,988 control chromosomes in the GnomAD database, including 16,555 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 0.44 (16555 hom., cov: 32)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.314

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCH1	NM_000161.3	c.510-2422T>C		intron_variant		ENST00000491895.7	NP_000152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7	c.510-2422T>C		intron_variant		1	NM_000161.3	ENSP00000419045.2

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66717 AN: 151870 Hom.: 16517 Cov.: 32

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.394

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.383

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

GnomAD4 genome AF: 0.440 AC: 66832 AN: 151988 Hom.: 16555 Cov.: 32 AF XY: 0.442 AC XY: 32858 AN XY: 74292

Gnomad4 AFR AF: 0.677

Gnomad4 AMR AF: 0.411

Gnomad4 ASJ AF: 0.198

Gnomad4 EAS AF: 0.395

Gnomad4 SAS AF: 0.248

Gnomad4 FIN AF: 0.463

Gnomad4 NFE AF: 0.330

Gnomad4 OTH AF: 0.385

Alfa AF: 0.411 Hom.: 1815

Bravo AF: 0.446

Asia WGS AF: 0.316 AC: 1096 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.5
DANN	Benign	0.41

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: rs10133662; hg19: chr14-55316270;