14-54902642-C-G

Variant names:

• chr14-54902642-C-G
• rs529381971
• NM_000161.3:c.22G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000161.3(GCH1):​c.22G>C​(p.Ala8Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,331,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A8T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: GCH1 NM_000161.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.443
• Publications: 2 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 30 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.5191 (below the threshold of 3.09). Trascript score misZ: 0.62455 (below the threshold of 3.09). GenCC associations: The gene is linked to GTP cyclohydrolase I deficiency, dystonia 5, GTP cyclohydrolase I deficiency with hyperphenylalaninemia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2281662).

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.22G>C	p.Ala8Pro	missense	Exon 1 of 6	NP_000152.1
	GCH1	NM_001024024.2		c.22G>C	p.Ala8Pro	missense	Exon 1 of 7	NP_001019195.1
	GCH1	NM_001024070.2		c.22G>C	p.Ala8Pro	missense	Exon 1 of 7	NP_001019241.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCH1	ENST00000491895.7	TSL:1 MANE Select	c.22G>C	p.Ala8Pro	missense	Exon 1 of 6	ENSP00000419045.2
	GCH1	ENST00000395514.5	TSL:1	c.22G>C	p.Ala8Pro	missense	Exon 1 of 7	ENSP00000378890.1
	GCH1	ENST00000543643.6	TSL:1	c.22G>C	p.Ala8Pro	missense	Exon 1 of 7	ENSP00000444011.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000150 AC: 2 AN: 1331040 Hom.: 0 Cov.: 32 AF XY: 0.00000152 AC XY: 1 AN XY: 655984

African (AFR) AF: 0.00 AC: 0 AN: 26792

American (AMR) AF: 0.00 AC: 0 AN: 27778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23332

East Asian (EAS) AF: 0.00 AC: 0 AN: 30018

South Asian (SAS) AF: 0.00 AC: 0 AN: 72834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3930

European-Non Finnish (NFE) AF: 0.00000190 AC: 2 AN: 1053774

Other (OTH) AF: 0.00 AC: 0 AN: 55056

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	GTP cyclohydrolase I deficiency;C1851920:Dystonia 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	16
DANN	Benign	0.87
DEOGEN2	Benign	0.37	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.23	T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	0.90	L
PhyloP100		0.44
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.35
Sift	Benign	0.14	T
Sift4G	Benign	0.29	T
Polyphen		0.38	B
Vest4		0.18
MutPred		0.25		Loss of MoRF binding (P = 0.0239)
MVP		0.64
MPC		1.3
ClinPred		0.21	T
GERP RS		1.2
PromoterAI		0.073	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.34
Mutation Taster		=98/2	polymorphism

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: rs529381971; hg19: chr14-55369360;