chr14-54902663-T-A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_000161.3(GCH1):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

GCH1
NM_000161.3 initiator_codon

Scores

6
2
8

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.96

Publications

1 publications found
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]
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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 40 pathogenic variants. Next in-frame start position is after 102 codons. Genomic position: 54902360. Lost 0.404 part of the original CDS.
PS1
Another start lost variant in NM_000161.3 (GCH1) was described as [Pathogenic] in ClinVar as 642685
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-54902663-T-A is Pathogenic according to our data. Variant chr14-54902663-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 465758.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GCH1NM_000161.3 linkc.1A>T p.Met1? initiator_codon_variant Exon 1 of 6 ENST00000491895.7 NP_000152.1 P30793-1A0A024R642

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GCH1ENST00000491895.7 linkc.1A>T p.Met1? initiator_codon_variant Exon 1 of 6 1 NM_000161.3 ENSP00000419045.2 P30793-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151968
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151968
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74224
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41406
American (AMR)
AF:
0.00
AC:
0
AN:
15264
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5162
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10604
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
312
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
67918
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

GTP cyclohydrolase I deficiency;C1851920:Dystonia 5 Pathogenic:1
Feb 23, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change affects the initiator methionine of the GCH1 mRNA. The next in-frame methionine is located at codon 102. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with autosomal dominant dopa-responsive dystonia (PMID: 9576537, 17557242, 20437540, 21935284, 22373569, 31213404). ClinVar contains an entry for this variant (Variation ID: 465758). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.46
CADD
Benign
19
DANN
Benign
0.92
DEOGEN2
Benign
0.38
T;T;.;T;.
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.28
FATHMM_MKL
Benign
0.49
N
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
0.95
D
PhyloP100
2.0
PROVEAN
Benign
-0.31
.;N;N;N;N
REVEL
Uncertain
0.58
Sift
Pathogenic
0.0
.;D;D;D;D
Sift4G
Benign
0.085
T;T;T;T;T
Polyphen
0.0010
B;B;B;B;B
Vest4
0.90
MutPred
0.99
Loss of methylation at K3 (P = 0.0509);Loss of methylation at K3 (P = 0.0509);Loss of methylation at K3 (P = 0.0509);Loss of methylation at K3 (P = 0.0509);Loss of methylation at K3 (P = 0.0509);
MVP
0.98
ClinPred
1.0
D
GERP RS
3.2
PromoterAI
-0.038
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.94
gMVP
0.60
Mutation Taster
=0/200
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555362907; hg19: chr14-55369381; API