rs2183081

Variant names:

• chr14-54870033-A-G
• rs2183081
• NM_000161.3:c.344-4597T>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.344-4597T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 151,918 control chromosomes in the GnomAD database, including 17,097 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 0.45 (17097 hom., cov: 31)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.934
• Publications: 6 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.668 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.344-4597T>C		intron	N/A	NP_000152.1
	GCH1	NM_001024024.2		c.344-4597T>C		intron	N/A	NP_001019195.1
	GCH1	NM_001024070.2		c.344-4597T>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.344-4597T>C		intron	N/A	ENSP00000419045.2
	GCH1	ENST00000395514.5	TSL:1	c.344-4597T>C		intron	N/A	ENSP00000378890.1
	GCH1	ENST00000543643.6	TSL:1	c.344-4597T>C		intron	N/A	ENSP00000444011.2

Frequencies

GnomAD3 genomes AF: 0.450 AC: 68295 AN: 151800 Hom.: 17052 Cov.: 31

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.412

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.548

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.396

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

GnomAD4 genome AF: 0.450 AC: 68411 AN: 151918 Hom.: 17097 Cov.: 31 AF XY: 0.453 AC XY: 33628 AN XY: 74254

African (AFR) AF: 0.674 AC: 27931 AN: 41414

American (AMR) AF: 0.412 AC: 6277 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 959 AN: 3466

East Asian (EAS) AF: 0.550 AC: 2841 AN: 5170

South Asian (SAS) AF: 0.411 AC: 1980 AN: 4814

European-Finnish (FIN) AF: 0.407 AC: 4297 AN: 10560

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

European-Non Finnish (NFE) AF: 0.335 AC: 22759 AN: 67930

Other (OTH) AF: 0.400 AC: 845 AN: 2112

Alfa AF: 0.356 Hom.: 3257

Bravo AF: 0.459

Asia WGS AF: 0.470 AC: 1633 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.3
DANN	Benign	0.61
PhyloP100		-0.93
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: rs2183081; hg19: chr14-55336751;