14-54861917-C-T

Variant names:

• chr14-54861917-C-T
• rs9671371
• NM_000161.3:c.454-2181G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• dystonia 5

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• GTP cyclohydrolase I deficiency with hyperphenylalaninemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P
• GTP cyclohydrolase I deficiency

  Inheritance: SD, AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GCH1	NM_000161.3	c.454-2181G>A		intron_variant	Intron 2 of 5	ENST00000491895.7	NP_000152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7	c.454-2181G>A		intron_variant	Intron 2 of 5	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

African (AFR) AF: 0.392 AC: 16233 AN: 41390

American (AMR) AF: 0.367 AC: 5603 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 652 AN: 3470

East Asian (EAS) AF: 0.363 AC: 1871 AN: 5160

South Asian (SAS) AF: 0.156 AC: 748 AN: 4810

European-Finnish (FIN) AF: 0.413 AC: 4352 AN: 10536

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21199 AN: 67964

Other (OTH) AF: 0.308 AC: 647 AN: 2104

Alfa AF: 0.322 Hom.: 3185

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
PhyloP100		-0.26
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9671371; hg19: chr14-55328635;