rs995999325

chr14-54902545-G-Achr14-54902545-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000161.3(GCH1):c.119C>T(p.Pro40Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P40R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCH1 NM_000161.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0610

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a chain GTP cyclohydrolase 1 (size 249) in uniprot entity GCH1_HUMAN there are 70 pathogenic changes around while only 7 benign (91%) in NM_000161.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.24412847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCH1	NM_000161.3	c.119C>T	p.Pro40Leu	missense_variant	1/6	ENST00000491895.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCH1	ENST00000491895.7	c.119C>T	p.Pro40Leu	missense_variant	1/6	1	NM_000161.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1392624 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 687688

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	16
Dann	Benign	0.95
DEOGEN2	Benign	0.38	T;T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Pathogenic	1.4	D
MutationAssessor	Benign	0.69	N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.76	T
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.046	B;B;P;B;B
Vest4		0.14
MutPred		0.27		Loss of glycosylation at P40 (P = 0.0112);Loss of glycosylation at P40 (P = 0.0112);Loss of glycosylation at P40 (P = 0.0112);Loss of glycosylation at P40 (P = 0.0112);Loss of glycosylation at P40 (P = 0.0112);
MVP		0.65
MPC		1.1
ClinPred		0.15	T
GERP RS		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.039
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs995999325; hg19: chr14-55369263;