Genetic Variant GCH1:p.Met1? (chr14-54902663-T-C) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000161.3(GCH1):c.1A>G(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 (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GCH1
NM_000161.3 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 1.96

Publications

0 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: 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

GCH1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 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.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-54902663-T-C is Pathogenic according to our data. Variant chr14-54902663-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 642685.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GCH1	NM_000161.3	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	NP_000152.1	P30793-1
GCH1	NM_001024024.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 7	NP_001019195.1	P30793-1
GCH1	NM_001024070.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 7	NP_001019241.1	P30793-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GCH1	ENST00000491895.7	TSL:1 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000419045.2	P30793-1
GCH1	ENST00000395514.5	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 7	ENSP00000378890.1	P30793-1
GCH1	ENST00000543643.6	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 7	ENSP00000444011.2	P30793-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1298112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

636880

African (AFR)

AF:

0.00

AC:

AN:

26226

American (AMR)

AF:

0.00

AC:

AN:

24732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21520

East Asian (EAS)

AF:

0.00

AC:

AN:

29444

South Asian (SAS)

AF:

0.00

AC:

AN:

68258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3816

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1036962

Other (OTH)

AF:

0.00

AC:

AN:

53730

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

GTP cyclohydrolase I deficiency;C1851920:Dystonia 5 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.37

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

1.0

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

PhyloP100

2.0

PROVEAN

Benign

-0.13

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.027

Polyphen

0.0020

Vest4

0.89

MutPred

1.0

Loss of methylation at K3 (P = 0.1519)

MVP

0.99

ClinPred

1.0

GERP RS

3.2

PromoterAI

0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.93

gMVP

0.73

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over