rs104894439

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_000161.3(GCH1):​c.3G>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

GCH1
NM_000161.3 start_lost

Scores

6
4
6

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.66
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-54902661-C-G is Pathogenic according to our data. Variant chr14-54902661-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 9277.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GCH1NM_000161.3 linkuse as main transcriptc.3G>C p.Met1? start_lost 1/6 ENST00000491895.7 NP_000152.1 P30793-1A0A024R642

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GCH1ENST00000491895.7 linkuse as main transcriptc.3G>C p.Met1? start_lost 1/61 NM_000161.3 ENSP00000419045.2 P30793-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Dystonia 5 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 01, 1998- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.24
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.38
T;T;.;T;.
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.058
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.90
.;D;D;.;D
M_CAP
Pathogenic
1.0
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D
MetaSVM
Pathogenic
1.2
D
PROVEAN
Benign
-0.20
.;N;N;N;N
REVEL
Uncertain
0.56
Sift
Pathogenic
0.0
.;D;D;D;D
Sift4G
Benign
0.21
T;T;T;T;T
Polyphen
0.0
B;B;B;B;B
Vest4
0.96
MutPred
1.0
Gain of catalytic residue at M1 (P = 0.0757);Gain of catalytic residue at M1 (P = 0.0757);Gain of catalytic residue at M1 (P = 0.0757);Gain of catalytic residue at M1 (P = 0.0757);Gain of catalytic residue at M1 (P = 0.0757);
MVP
0.98
ClinPred
1.0
D
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.95
gMVP
0.70

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs104894439; hg19: chr14-55369379; API