Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The ENST00000491895.7(GCH1):c.211C>T(p.Leu71Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000417 in 1,612,774 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 3 hom. )

Consequence

GCH1
ENST00000491895.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.04

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

GCH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 14-54902453-G-A is Benign according to our data. Variant chr14-54902453-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.04 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00215 (327/152314) while in subpopulation AFR AF = 0.00717 (298/41582). AF 95% confidence interval is 0.0065. There are 1 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 SD,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000491895.7. 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.211C>T	p.Leu71Leu	synonymous	Exon 1 of 6	NP_000152.1
GCH1	NM_001024024.2		c.211C>T	p.Leu71Leu	synonymous	Exon 1 of 7	NP_001019195.1
GCH1	NM_001024070.2		c.211C>T	p.Leu71Leu	synonymous	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.211C>T	p.Leu71Leu	synonymous	Exon 1 of 6	ENSP00000419045.2
GCH1	ENST00000395514.5	TSL:1	c.211C>T	p.Leu71Leu	synonymous	Exon 1 of 7	ENSP00000378890.1
GCH1	ENST00000543643.6	TSL:1	c.211C>T	p.Leu71Leu	synonymous	Exon 1 of 7	ENSP00000444011.2

Frequencies

GnomAD3 genomes

AF:

0.00213

AC:

324

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00712

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000577

AC:

143

AN:

247934

AF XY:

0.000415

show subpopulations

Gnomad AFR exome

AF:

0.00669

Gnomad AMR exome

AF:

0.000698

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000449

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000237

AC:

346

AN:

1460460

Hom.:

Cov.:

AF XY:

0.000241

AC XY:

175

AN XY:

726570

show subpopulations

African (AFR)

AF:

0.00675

AC:

226

AN:

33460

American (AMR)

AF:

0.000761

AC:

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52586

Middle Eastern (MID)

AF:

0.00296

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1111712

Other (OTH)

AF:

0.000829

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00215

AC:

327

AN:

152314

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00717

AC:

298

AN:

41582

American (AMR)

AF:

0.00144

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68012

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000950

Hom.:

Bravo

AF:

0.00231

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

3.0

PromoterAI

-0.025

Neutral

(source)

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

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

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over