NM_000161.3:c.344-16715G>A

Variant names:

• chr14-54882151-C-T
• rs11158026
• NM_000161.3:c.344-16715G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000161.3(GCH1):​c.344-16715G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 152,036 control chromosomes in the GnomAD database, including 17,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.45 (17006 hom., cov: 32)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.69

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-54882151-C-T is Benign according to our data. Variant chr14-54882151-C-T is described in ClinVar as [Benign]. Clinvar id is 1169986.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCH1	NM_000161.3	c.344-16715G>A		intron_variant	Intron 1 of 5	ENST00000491895.7	NP_000152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7	c.344-16715G>A		intron_variant	Intron 1 of 5	1	NM_000161.3	ENSP00000419045.2

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68083 AN: 151918 Hom.: 16961 Cov.: 32

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.545

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.392

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

GnomAD4 genome AF: 0.449 AC: 68200 AN: 152036 Hom.: 17006 Cov.: 32 AF XY: 0.451 AC XY: 33521 AN XY: 74298

Gnomad4 AFR AF: 0.673

Gnomad4 AMR AF: 0.410

Gnomad4 ASJ AF: 0.276

Gnomad4 EAS AF: 0.546

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.333

Gnomad4 OTH AF: 0.396

Alfa AF: 0.292 Hom.: 2458

Bravo AF: 0.457

Asia WGS AF: 0.467 AC: 1623 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GTP cyclohydrolase I deficiency;C1851920:Dystonia 5 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0020
DANN	Benign	0.69

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: rs11158026; hg19: chr14-55348869;