rs8004018

Variant names:

• chr14-54883978-A-G
• rs8004018
• NM_000161.3:c.343+18343T>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.343+18343T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 152,168 control chromosomes in the GnomAD database, including 4,500 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 0.21 (4500 hom., cov: 32)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.04
• Publications: 16 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.402 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.343+18343T>C		intron	N/A	NP_000152.1
	GCH1	NM_001024024.2		c.343+18343T>C		intron	N/A	NP_001019195.1
	GCH1	NM_001024070.2		c.343+18343T>C		intron	N/A	NP_001019241.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCH1	ENST00000491895.7	TSL:1 MANE Select	c.343+18343T>C		intron	N/A	ENSP00000419045.2
	GCH1	ENST00000395514.5	TSL:1	c.343+18343T>C		intron	N/A	ENSP00000378890.1
	GCH1	ENST00000543643.6	TSL:1	c.343+18343T>C		intron	N/A	ENSP00000444011.2

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31570 AN: 152050 Hom.: 4480 Cov.: 32

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.159

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

GnomAD4 genome AF: 0.208 AC: 31623 AN: 152168 Hom.: 4500 Cov.: 32 AF XY: 0.208 AC XY: 15505 AN XY: 74404

African (AFR) AF: 0.386 AC: 16009 AN: 41464

American (AMR) AF: 0.148 AC: 2264 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 432 AN: 3472

East Asian (EAS) AF: 0.417 AC: 2156 AN: 5176

South Asian (SAS) AF: 0.239 AC: 1151 AN: 4816

European-Finnish (FIN) AF: 0.108 AC: 1144 AN: 10620

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7991 AN: 68018

Other (OTH) AF: 0.165 AC: 349 AN: 2112

Alfa AF: 0.147 Hom.: 8268

Bravo AF: 0.219

Asia WGS AF: 0.316 AC: 1098 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		1.0
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: rs8004018; hg19: chr14-55350696;