rs8010282

Variant names:

• chr14-54863537-A-G
• rs8010282
• NM_000161.3:c.453+1790T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000161.3(GCH1):​c.453+1790T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 142,180 control chromosomes in the GnomAD database, including 3,039 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 0.17 (3039 hom., cov: 24)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18
• Publications: 3 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCH1	NM_000161.3	c.453+1790T>C		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.453+1790T>C		intron_variant	Intron 2 of 5	1	NM_000161.3	ENSP00000419045.2

Frequencies

GnomAD3 genomes AF: 0.165 AC: 23491 AN: 142096 Hom.: 3024 Cov.: 24

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.0930

Gnomad AMR AF: 0.0703

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.0628

Gnomad MID AF: 0.103

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.129

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

GnomAD4 genome AF: 0.165 AC: 23517 AN: 142180 Hom.: 3039 Cov.: 24 AF XY: 0.162 AC XY: 11207 AN XY: 69162

African (AFR) AF: 0.347 AC: 12453 AN: 35910

American (AMR) AF: 0.0701 AC: 1013 AN: 14460

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 395 AN: 3434

East Asian (EAS) AF: 0.193 AC: 961 AN: 4968

South Asian (SAS) AF: 0.157 AC: 695 AN: 4436

European-Finnish (FIN) AF: 0.0628 AC: 566 AN: 9008

Middle Eastern (MID) AF: 0.0922 AC: 26 AN: 282

European-Non Finnish (NFE) AF: 0.106 AC: 7055 AN: 66786

Other (OTH) AF: 0.135 AC: 271 AN: 2014

Alfa AF: 0.157 Hom.: 308

Asia WGS AF: 0.197 AC: 655 AN: 3322

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.3
DANN	Benign	0.61
PhyloP100		1.2
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: rs8010282; hg19: chr14-55330255;