chr14-54847116-T-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate

The NM_000161.3(GCH1):c.524A>T(p.Tyr175Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 991,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y175C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

GCH1
NM_000161.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 3.31

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: 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

GCH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000161.3

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=0.23509875).

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
GCH1	NM_000161.3	MANE Select	c.524A>T	p.Tyr175Phe	missense	Exon 4 of 6	NP_000152.1
GCH1	NM_001024024.2		c.524A>T	p.Tyr175Phe	missense	Exon 4 of 7	NP_001019195.1
GCH1	NM_001024070.2		c.524A>T	p.Tyr175Phe	missense	Exon 4 of 7	NP_001019241.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GCH1	ENST00000491895.7	TSL:1 MANE Select	c.524A>T	p.Tyr175Phe	missense	Exon 4 of 6	ENSP00000419045.2
GCH1	ENST00000395514.5	TSL:1	c.524A>T	p.Tyr175Phe	missense	Exon 4 of 7	ENSP00000378890.1
GCH1	ENST00000543643.6	TSL:1	c.524A>T	p.Tyr175Phe	missense	Exon 4 of 7	ENSP00000444011.2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152262

Hom.:

Cov.:

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000282

AC:

AN:

212682

AF XY:

0.00000870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000646

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000262

AC:

AN:

838764

Hom.:

Cov.:

AF XY:

0.0000185

AC XY:

AN XY:

432982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21222

American (AMR)

AF:

0.00

AC:

AN:

38144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20486

East Asian (EAS)

AF:

0.00

AC:

AN:

34810

South Asian (SAS)

AF:

0.00

AC:

AN:

69302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4390

European-Non Finnish (NFE)

AF:

0.0000371

AC:

AN:

566416

Other (OTH)

AF:

0.0000264

AC:

AN:

37900

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.407

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000831

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

GCH1-related disorder (1)

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

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.044

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Uncertain

0.61

Eigen

Benign

-0.21

Eigen_PC

Benign

0.026

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.24

MetaSVM

Pathogenic

1.2

MutationAssessor

Benign

-0.10

PhyloP100

3.3

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.67

REVEL

Uncertain

0.52

Sift

Benign

0.93

Sift4G

Benign

0.97

Polyphen

0.29

Vest4

0.33

MVP

0.63

MPC

1.4

ClinPred

0.19

GERP RS

5.9

Varity_R

0.43

gMVP

0.93

Mutation Taster

=50/50

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over