14-54881400-C-T

Variant names:

• chr14-54881400-C-T
• rs3783637
• NM_000161.3:c.344-15964G>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.344-15964G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 152,064 control chromosomes in the GnomAD database, including 1,504 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 0.13 (1504 hom., cov: 32)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.62
• Publications: 39 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCH1	NM_000161.3	c.344-15964G>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.344-15964G>A		intron_variant	Intron 1 of 5	1	NM_000161.3	ENSP00000419045.2

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19252 AN: 151944 Hom.: 1495 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.237

Gnomad FIN AF: 0.107

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.106

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

GnomAD4 genome AF: 0.127 AC: 19285 AN: 152064 Hom.: 1504 Cov.: 32 AF XY: 0.130 AC XY: 9663 AN XY: 74314

African (AFR) AF: 0.104 AC: 4319 AN: 41504

American (AMR) AF: 0.119 AC: 1818 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 429 AN: 3470

East Asian (EAS) AF: 0.416 AC: 2144 AN: 5156

South Asian (SAS) AF: 0.238 AC: 1145 AN: 4806

European-Finnish (FIN) AF: 0.107 AC: 1131 AN: 10556

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7937 AN: 67978

Other (OTH) AF: 0.113 AC: 238 AN: 2112

Alfa AF: 0.123 Hom.: 5863

Bravo AF: 0.126

Asia WGS AF: 0.294 AC: 1023 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.65
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3783637; hg19: chr14-55348118;