14-54854067-G-A

Variant names:

• chr14-54854067-G-A
• rs2878168
• NM_000161.3:c.509+5614C>T

Variant summary

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

The NM_000161.3(GCH1):​c.509+5614C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 151,982 control chromosomes in the GnomAD database, including 6,215 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 0.27 (6215 hom., cov: 32)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.753
• Publications: 5 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: Genomics England PanelApp, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• GTP cyclohydrolase I deficiency with hyperphenylalaninemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.385 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCH1	NM_000161.3	MANE Select	c.509+5614C>T		intron	N/A	NP_000152.1	P30793-1
	GCH1	NM_001024024.2		c.509+5614C>T		intron	N/A	NP_001019195.1	P30793-1
	GCH1	NM_001024070.2		c.509+5614C>T		intron	N/A	NP_001019241.1	P30793-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCH1	ENST00000491895.7	TSL:1 MANE Select	c.509+5614C>T		intron	N/A	ENSP00000419045.2	P30793-1
	GCH1	ENST00000395514.5	TSL:1	c.509+5614C>T		intron	N/A	ENSP00000378890.1	P30793-1
	GCH1	ENST00000543643.6	TSL:1	c.509+5614C>T		intron	N/A	ENSP00000444011.2	P30793-4

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41262 AN: 151864 Hom.: 6201 Cov.: 32

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.247

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.251

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

GnomAD4 genome AF: 0.272 AC: 41336 AN: 151982 Hom.: 6215 Cov.: 32 AF XY: 0.272 AC XY: 20204 AN XY: 74260

African (AFR) AF: 0.390 AC: 16174 AN: 41422

American (AMR) AF: 0.317 AC: 4841 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 509 AN: 3472

East Asian (EAS) AF: 0.363 AC: 1881 AN: 5176

South Asian (SAS) AF: 0.140 AC: 677 AN: 4820

European-Finnish (FIN) AF: 0.247 AC: 2595 AN: 10514

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.203 AC: 13822 AN: 67986

Other (OTH) AF: 0.249 AC: 526 AN: 2116

Alfa AF: 0.218 Hom.: 5680

Bravo AF: 0.285

Asia WGS AF: 0.225 AC: 784 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.7
DANN	Benign	0.74
PhyloP100		0.75
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: rs2878168; hg19: chr14-55320785;