chr14-54882151-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 54 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 -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000161.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCH1	NM_000161.3	MANE Select	c.344-16715G>A		intron	N/A	NP_000152.1
	GCH1	NM_001424105.1		c.-561G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_001411034.1
	GCH1	NM_001424105.1		c.-561G>A		5_prime_UTR	Exon 1 of 6	NP_001411034.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCH1	ENST00000491895.7	TSL:1 MANE Select	c.344-16715G>A		intron	N/A	ENSP00000419045.2
	GCH1	ENST00000395514.5	TSL:1	c.344-16715G>A		intron	N/A	ENSP00000378890.1
	GCH1	ENST00000543643.6	TSL:1	c.344-16715G>A		intron	N/A	ENSP00000444011.2

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

African (AFR) AF: 0.673 AC: 27921 AN: 41480

American (AMR) AF: 0.410 AC: 6249 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 956 AN: 3466

East Asian (EAS) AF: 0.546 AC: 2824 AN: 5168

South Asian (SAS) AF: 0.412 AC: 1984 AN: 4818

European-Finnish (FIN) AF: 0.407 AC: 4291 AN: 10550

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22614 AN: 67976

Other (OTH) AF: 0.396 AC: 837 AN: 2114

Alfa AF: 0.354 Hom.: 17867

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0020
DANN	Benign	0.69
PhyloP100		-3.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11158026; hg19: chr14-55348869;