rs3783638

Variant names:

• chr14-54881655-G-A
• rs3783638
• NM_000161.3:c.344-16219C>T

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.344-16219C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,060 control chromosomes in the GnomAD database, including 4,893 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.21 (4893 hom., cov: 32)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0630
• Publications: 15 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=-0.82).
• BP6: Variant 14-54881655-G-A is Benign according to our data. Variant chr14-54881655-G-A is described in ClinVar as Benign. ClinVar VariationId is 3256824.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.405 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCH1	NM_000161.3	c.344-16219C>T		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.344-16219C>T		intron_variant	Intron 1 of 5	1	NM_000161.3	ENSP00000419045.2

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32584 AN: 151944 Hom.: 4872 Cov.: 32

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.414

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.162

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

GnomAD4 genome AF: 0.215 AC: 32645 AN: 152060 Hom.: 4893 Cov.: 32 AF XY: 0.215 AC XY: 15990 AN XY: 74354

African (AFR) AF: 0.410 AC: 16968 AN: 41406

American (AMR) AF: 0.152 AC: 2323 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 432 AN: 3466

East Asian (EAS) AF: 0.415 AC: 2151 AN: 5180

South Asian (SAS) AF: 0.240 AC: 1155 AN: 4822

European-Finnish (FIN) AF: 0.107 AC: 1134 AN: 10578

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 292

European-Non Finnish (NFE) AF: 0.118 AC: 8001 AN: 68010

Other (OTH) AF: 0.168 AC: 354 AN: 2112

Alfa AF: 0.160 Hom.: 494

Bravo AF: 0.226

Asia WGS AF: 0.316 AC: 1096 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 31, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 27% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 25. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.7
DANN	Benign	0.59
PhyloP100		-0.063
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: rs3783638; hg19: chr14-55348373;