dbSNP rs2878169: GCH1:c.509+406C>A (chr14-54859275-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000161.3(GCH1):c.509+406C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0768 in 242,470 control chromosomes in the GnomAD database, including 1,126 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.073 ( 640 hom., cov: 32)

Exomes 𝑓: 0.083 ( 486 hom. )

Consequence

GCH1
NM_000161.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.249

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 links:

RNU6ATAC9P (HGNC:46908): (RNA, U6atac small nuclear 9, pseudogene)

RNU6ATAC9P links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCH1	NM_000161.3 link	c.509+406C>A		intron_variant	Intron 3 of 5	ENST00000491895.7	NP_000152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7 link	c.509+406C>A		intron_variant	Intron 3 of 5	1	NM_000161.3	ENSP00000419045.2

Frequencies

GnomAD3 genomes

AF:

0.0730

AC:

11097

AN:

152114

Hom.:

640

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0164

Gnomad AMI

AF:

0.152

Gnomad AMR

AF:

0.0504

Gnomad ASJ

AF:

0.0418

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0180

Gnomad FIN

AF:

0.166

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.109

Gnomad OTH

AF:

0.0602

GnomAD4 exome

AF:

0.0835

AC:

7534

AN:

90240

Hom.:

486

Cov.:

AF XY:

0.0799

AC XY:

3772

AN XY:

47216

show subpopulations

African (AFR)

AF:

0.0132

AC:

AN:

3170

American (AMR)

AF:

0.0431

AC:

194

AN:

4498

Ashkenazi Jewish (ASJ)

AF:

0.0491

AC:

104

AN:

2118

East Asian (EAS)

AF:

0.00

AC:

AN:

5012

South Asian (SAS)

AF:

0.0197

AC:

247

AN:

12570

European-Finnish (FIN)

AF:

0.142

AC:

560

AN:

3940

Middle Eastern (MID)

AF:

0.0193

AC:

AN:

362

European-Non Finnish (NFE)

AF:

0.111

AC:

5951

AN:

53770

Other (OTH)

AF:

0.0894

AC:

429

AN:

4800

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

303

605

908

1210

1513

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.0729

AC:

11096

AN:

152230

Hom.:

640

Cov.:

AF XY:

0.0740

AC XY:

5505

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0163

AC:

678

AN:

41552

American (AMR)

AF:

0.0503

AC:

769

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0418

AC:

145

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0180

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.166

AC:

1755

AN:

10590

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.109

AC:

7392

AN:

67996

Other (OTH)

AF:

0.0596

AC:

126

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

511

1022

1533

2044

2555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<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:

0.108

Hom.:

168

Bravo

AF:

0.0603

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

3.6

(source)

DANN

Benign

0.51

PhyloP100

0.25

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over