chr14-54902642-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP2BP4_ModerateBS1_Supporting

The NM_000161.3(GCH1):c.22G>T(p.Ala8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000115 in 1,483,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. A8T) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

GCH1
NM_000161.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.443

Publications

2 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: Likely_benign. The variant received -2 ACMG points.

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=0.15217066).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000012 (16/1331040) while in subpopulation SAS AF = 0.000206 (15/72832). AF 95% confidence interval is 0.000126. There are 0 homozygotes in GnomAdExome4. There are 12 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.22G>T	p.Ala8Ser	missense	Exon 1 of 6	NP_000152.1
GCH1	NM_001024024.2		c.22G>T	p.Ala8Ser	missense	Exon 1 of 7	NP_001019195.1
GCH1	NM_001024070.2		c.22G>T	p.Ala8Ser	missense	Exon 1 of 7	NP_001019241.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GCH1	ENST00000491895.7	TSL:1 MANE Select	c.22G>T	p.Ala8Ser	missense	Exon 1 of 6	ENSP00000419045.2
GCH1	ENST00000395514.5	TSL:1	c.22G>T	p.Ala8Ser	missense	Exon 1 of 7	ENSP00000378890.1
GCH1	ENST00000543643.6	TSL:1	c.22G>T	p.Ala8Ser	missense	Exon 1 of 7	ENSP00000444011.2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152076

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000231

AC:

AN:

86518

AF XY:

0.0000203

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000120

AC:

AN:

1331040

Hom.:

Cov.:

AF XY:

0.0000183

AC XY:

AN XY:

655982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26792

American (AMR)

AF:

0.00

AC:

AN:

27778

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23332

East Asian (EAS)

AF:

0.00

AC:

AN:

30020

South Asian (SAS)

AF:

0.000206

AC:

AN:

72832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3930

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1053774

Other (OTH)

AF:

0.0000182

AC:

AN:

55056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41552

American (AMR)

AF:

0.00

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.36

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.64

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.15

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.2

PhyloP100

0.44

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.060

REVEL

Uncertain

0.38

Sift

Benign

0.56

Sift4G

Benign

0.73

Polyphen

0.018

Vest4

0.10

MutPred

0.24

Gain of phosphorylation at A8 (P = 0.0024)

MVP

0.67

MPC

0.95

ClinPred

0.029

GERP RS

1.2

PromoterAI

0.038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.071

gMVP

0.23

Mutation Taster

=96/4

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over