chr14-54842973-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_000161.3(GCH1):c.*1044G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000367 in 749,840 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00087 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

GCH1
NM_000161.3 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.121

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
GTP cyclohydrolase I deficiency
Inheritance: AD, SD Classification: DEFINITIVE Submitted by: Illumina, ClinGen
GTP cyclohydrolase I deficiency with hyperphenylalaninemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P

GCH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 14-54842973-C-T is Benign according to our data. Variant chr14-54842973-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 883618.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000867 (132/152240) while in subpopulation AFR AF = 0.00272 (113/41528). AF 95% confidence interval is 0.00231. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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	Effect	Exon Rank	Protein	UniProt
GCH1	NM_000161.3	MANE Select	c.*1044G>A	3_prime_UTR	Exon 6 of 6	NP_000152.1	P30793-1
GCH1	NM_001024024.2		c.*98G>A	3_prime_UTR	Exon 7 of 7	NP_001019195.1	P30793-1
GCH1	NM_001024070.2		c.*94G>A	3_prime_UTR	Exon 7 of 7	NP_001019241.1	P30793-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GCH1	ENST00000491895.7	TSL:1 MANE Select	c.*1044G>A	3_prime_UTR	Exon 6 of 6	ENSP00000419045.2	P30793-1
GCH1	ENST00000395514.5	TSL:1	c.*98G>A	3_prime_UTR	Exon 7 of 7	ENSP00000378890.1	P30793-1
GCH1	ENST00000543643.6	TSL:1	c.*94G>A	3_prime_UTR	Exon 7 of 7	ENSP00000444011.2	P30793-4

Frequencies

GnomAD3 genomes

AF:

0.000822

AC:

125

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000239

AC:

143

AN:

597600

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

324310

show subpopulations

African (AFR)

AF:

0.00222

AC:

AN:

16198

American (AMR)

AF:

0.000193

AC:

AN:

36286

Ashkenazi Jewish (ASJ)

AF:

0.00345

AC:

AN:

19738

East Asian (EAS)

AF:

0.00

AC:

AN:

35396

South Asian (SAS)

AF:

0.00

AC:

AN:

61320

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4028

European-Non Finnish (NFE)

AF:

0.0000674

AC:

AN:

341056

Other (OTH)

AF:

0.000283

AC:

AN:

31768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000867

AC:

132

AN:

152240

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00272

AC:

113

AN:

41528

American (AMR)

AF:

0.000327

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2114

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:

0.000832

Hom.:

Bravo

AF:

0.00101

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dystonia 5 (1)

GTP cyclohydrolase I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

8.1

(source)

DANN

Benign

0.60

PhyloP100

0.12

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over