rs41298432

Variant names:

• chr14-54902596-G-A
• rs41298432
• NM_000161.3:c.68C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000161.3(GCH1):​c.68C>T​(p.Pro23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,500,604 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P23P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (27 hom.)
• Consequence: GCH1 NM_000161.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 0.396
• Publications: 12 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.

• 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=0.0065107644).
• BP6: Variant 14-54902596-G-A is Benign according to our data. Variant chr14-54902596-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 313398.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00382 (582/152242) while in subpopulation NFE AF = 0.0064 (435/67990). AF 95% confidence interval is 0.0059. There are 1 homozygotes in GnomAd4. There are 266 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 27 SD,AD,AR gene

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.68C>T	p.Pro23Leu	missense	Exon 1 of 6	NP_000152.1	P30793-1
	GCH1	NM_001024024.2		c.68C>T	p.Pro23Leu	missense	Exon 1 of 7	NP_001019195.1	P30793-1
	GCH1	NM_001024070.2		c.68C>T	p.Pro23Leu	missense	Exon 1 of 7	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.68C>T	p.Pro23Leu	missense	Exon 1 of 6	ENSP00000419045.2	P30793-1
	GCH1	ENST00000395514.5	TSL:1	c.68C>T	p.Pro23Leu	missense	Exon 1 of 7	ENSP00000378890.1	P30793-1
	GCH1	ENST00000543643.6	TSL:1	c.68C>T	p.Pro23Leu	missense	Exon 1 of 7	ENSP00000444011.2	P30793-4

Frequencies

GnomAD3 genomes AF: 0.00383 AC: 582 AN: 152130 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00640

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00426 AC: 429 AN: 100738 AF XY: 0.00403

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000855

Gnomad NFE exome AF: 0.00637

Gnomad OTH exome AF: 0.00465

GnomAD4 exome AF: 0.00513 AC: 6918 AN: 1348362 Hom.: 27 Cov.: 32 AF XY: 0.00500 AC XY: 3325 AN XY: 664528

African (AFR) AF: 0.000779 AC: 21 AN: 26956

American (AMR) AF: 0.00261 AC: 75 AN: 28728

Ashkenazi Jewish (ASJ) AF: 0.0120 AC: 280 AN: 23374

East Asian (EAS) AF: 0.00 AC: 0 AN: 30778

South Asian (SAS) AF: 0.00280 AC: 206 AN: 73652

European-Finnish (FIN) AF: 0.000690 AC: 32 AN: 46362

Middle Eastern (MID) AF: 0.00812 AC: 33 AN: 4062

European-Non Finnish (NFE) AF: 0.00564 AC: 5977 AN: 1058930

Other (OTH) AF: 0.00530 AC: 294 AN: 55520

GnomAD4 genome AF: 0.00382 AC: 582 AN: 152242 Hom.: 1 Cov.: 33 AF XY: 0.00357 AC XY: 266 AN XY: 74436

African (AFR) AF: 0.000866 AC: 36 AN: 41574

American (AMR) AF: 0.00379 AC: 58 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4832

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10600

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00640 AC: 435 AN: 67990

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00568 Hom.: 0

Bravo AF: 0.00399

ExAC AF: 0.00191 AC: 85

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	GTP cyclohydrolase I deficiency (2)
-	1	1	GTP cyclohydrolase I deficiency;C1851920:Dystonia 5 (2)
-	-	1	Dystonia 5 (1)
-	-	1	GCH1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	16
DANN	Benign	0.85
DEOGEN2	Benign	0.41	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0065	T
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Benign	0.60	N
PhyloP100		0.40
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.61
Sift	Benign	0.42	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.088
MVP		1.0
MPC		1.1
ClinPred		0.0032	T
GERP RS		0.20
PromoterAI		-0.061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.36
Mutation Taster		=100/0	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: rs41298432; hg19: chr14-55369314; COSMIC: COSV54302103; COSMIC: COSV54302103;