rs8004445

Variant names:

• chr14-54883948-G-T
• rs8004445
• NM_000161.3:c.343+18373C>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.343+18373C>A 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 152,084 control chromosomes in the GnomAD database, including 4,901 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 (4901 hom., cov: 32)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53
• Publications: 8 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.404 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+18373C>A		intron	N/A	NP_000152.1
	GCH1	NM_001024024.2		c.343+18373C>A		intron	N/A	NP_001019195.1
	GCH1	NM_001024070.2		c.343+18373C>A		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+18373C>A		intron	N/A	ENSP00000419045.2
	GCH1	ENST00000395514.5	TSL:1	c.343+18373C>A		intron	N/A	ENSP00000378890.1
	GCH1	ENST00000543643.6	TSL:1	c.343+18373C>A		intron	N/A	ENSP00000444011.2

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32592 AN: 151968 Hom.: 4879 Cov.: 32

Gnomad AFR AF: 0.410

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.163

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

GnomAD4 genome AF: 0.215 AC: 32655 AN: 152084 Hom.: 4901 Cov.: 32 AF XY: 0.215 AC XY: 15988 AN XY: 74340

African (AFR) AF: 0.410 AC: 16977 AN: 41442

American (AMR) AF: 0.152 AC: 2325 AN: 15284

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

East Asian (EAS) AF: 0.416 AC: 2148 AN: 5160

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

European-Finnish (FIN) AF: 0.108 AC: 1139 AN: 10594

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 7997 AN: 68000

Other (OTH) AF: 0.169 AC: 357 AN: 2110

Alfa AF: 0.175 Hom.: 475

Bravo AF: 0.227

Asia WGS AF: 0.318 AC: 1105 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.20
DANN	Benign	0.30
PhyloP100		-1.5
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: rs8004445; hg19: chr14-55350666;