chr14-54856133-T-C

Variant names:

• chr14-54856133-T-C
• rs7155309
• NM_000161.3:c.509+3548A>G

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+3548A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 152,102 control chromosomes in the GnomAD database, including 3,742 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 0.22 (3742 hom., cov: 32)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.101
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 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+3548A>G		intron	N/A	NP_000152.1	P30793-1
	GCH1	NM_001024024.2		c.509+3548A>G		intron	N/A	NP_001019195.1	P30793-1
	GCH1	NM_001024070.2		c.509+3548A>G		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+3548A>G		intron	N/A	ENSP00000419045.2	P30793-1
	GCH1	ENST00000395514.5	TSL:1	c.509+3548A>G		intron	N/A	ENSP00000378890.1	P30793-1
	GCH1	ENST00000543643.6	TSL:1	c.509+3548A>G		intron	N/A	ENSP00000444011.2	P30793-4

Frequencies

GnomAD3 genomes AF: 0.217 AC: 33033 AN: 151984 Hom.: 3738 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.203

Gnomad OTH AF: 0.216

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

GnomAD4 genome AF: 0.217 AC: 33072 AN: 152102 Hom.: 3742 Cov.: 32 AF XY: 0.220 AC XY: 16378 AN XY: 74320

African (AFR) AF: 0.203 AC: 8436 AN: 41510

American (AMR) AF: 0.295 AC: 4504 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 508 AN: 3472

East Asian (EAS) AF: 0.356 AC: 1837 AN: 5154

South Asian (SAS) AF: 0.135 AC: 653 AN: 4826

European-Finnish (FIN) AF: 0.246 AC: 2603 AN: 10576

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

European-Non Finnish (NFE) AF: 0.203 AC: 13769 AN: 67966

Other (OTH) AF: 0.214 AC: 452 AN: 2110

Alfa AF: 0.169 Hom.: 825

Bravo AF: 0.223

Asia WGS AF: 0.203 AC: 707 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.4
DANN	Benign	0.70
PhyloP100		0.10
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: rs7155309; hg19: chr14-55322851;