chr14-54843774-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001024070.2(GCH1):c.*12+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,613,118 control chromosomes in the GnomAD database, including 37,505 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.22 ( 3819 hom., cov: 33)

Exomes 𝑓: 0.21 ( 33686 hom. )

Consequence

GCH1
NM_001024070.2 splice_region, intron

Scores

Splicing: ADA: 0.00001206

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.63

Publications

63 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 14-54843774-G-A is Benign according to our data. Variant chr14-54843774-G-A is described in ClinVar as Benign. ClinVar VariationId is 313386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024070.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GCH1	NM_000161.3	MANE Select	c.*243C>T	3_prime_UTR	Exon 6 of 6	NP_000152.1	P30793-1
GCH1	NM_001424105.1		c.*243C>T	3_prime_UTR	Exon 6 of 6	NP_001411034.1
GCH1	NM_001024024.2		c.*16+227C>T	intron	N/A	NP_001019195.1	P30793-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GCH1	ENST00000491895.7	TSL:1 MANE Select	c.*243C>T	3_prime_UTR	Exon 6 of 6	ENSP00000419045.2	P30793-1
GCH1	ENST00000395514.5	TSL:1	c.*16+227C>T	intron	N/A	ENSP00000378890.1	P30793-1
GCH1	ENST00000543643.6	TSL:1	c.*12+8C>T	splice_region intron	N/A	ENSP00000444011.2	P30793-4

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33387

AN:

151942

Hom.:

3815

Cov.:

show subpopulations

Gnomad AFR

AF:

0.212

Gnomad AMI

AF:

0.307

Gnomad AMR

AF:

0.295

Gnomad ASJ

AF:

0.146

Gnomad EAS

AF:

0.354

Gnomad SAS

AF:

0.131

Gnomad FIN

AF:

0.246

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.203

Gnomad OTH

AF:

0.219

GnomAD2 exomes

AF:

0.219

AC:

54642

AN:

250038

AF XY:

0.209

show subpopulations

Gnomad AFR exome

AF:

0.206

Gnomad AMR exome

AF:

0.308

Gnomad ASJ exome

AF:

0.146

Gnomad EAS exome

AF:

0.359

Gnomad FIN exome

AF:

0.245

Gnomad NFE exome

AF:

0.198

Gnomad OTH exome

AF:

0.205

GnomAD4 exome

AF:

0.210

AC:

306321

AN:

1461058

Hom.:

33686

Cov.:

AF XY:

0.205

AC XY:

149338

AN XY:

726832

show subpopulations

African (AFR)

AF:

0.209

AC:

6977

AN:

33458

American (AMR)

AF:

0.307

AC:

13726

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.147

AC:

3828

AN:

26122

East Asian (EAS)

AF:

0.387

AC:

15365

AN:

39674

South Asian (SAS)

AF:

0.130

AC:

11221

AN:

86200

European-Finnish (FIN)

AF:

0.245

AC:

13070

AN:

53412

Middle Eastern (MID)

AF:

0.138

AC:

794

AN:

5766

European-Non Finnish (NFE)

AF:

0.206

AC:

229051

AN:

1111360

Other (OTH)

AF:

0.204

AC:

12289

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

12103

24206

36309

48412

60515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8190

16380

24570

32760

40950

<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:

0.220

AC:

33426

AN:

152060

Hom.:

3819

Cov.:

AF XY:

0.223

AC XY:

16559

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.212

AC:

8782

AN:

41460

American (AMR)

AF:

0.295

AC:

4515

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.146

AC:

508

AN:

3468

East Asian (EAS)

AF:

0.355

AC:

1837

AN:

5168

South Asian (SAS)

AF:

0.132

AC:

634

AN:

4818

European-Finnish (FIN)

AF:

0.246

AC:

2595

AN:

10560

Middle Eastern (MID)

AF:

0.102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.203

AC:

13788

AN:

67986

Other (OTH)

AF:

0.217

AC:

457

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1355

2709

4064

5418

6773

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

348

696

1044

1392

1740

<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:

0.207

Hom.:

6360

Bravo

AF:

0.226

Asia WGS

AF:

0.202

AC:

703

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dystonia 5 (2)

GTP cyclohydrolase I deficiency (2)

not specified (2)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.30

(source)

DANN

Benign

0.40

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000012

dbscSNV1_RF

Benign

0.0080

SpliceAI score (max)

0.12

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over