Variant rs104894442 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000161.3(GCH1):c.747G>C(p.Arg249Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GCH1
NM_000161.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 0.448

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:

GCH1 (HGNC:):

GCH1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a chain GTP cyclohydrolase 1 (size 249) in uniprot entity GCH1_HUMAN there are 25 pathogenic changes around while only 3 benign (89%) in NM_000161.3

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCH1	NM_000161.3 linkuse as main transcript	c.747G>C	p.Arg249Ser	missense_variant	6/6	ENST00000491895.7	NP_000152.1	P30793-1A0A024R642

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7 linkuse as main transcript	c.747G>C	p.Arg249Ser	missense_variant	6/6	1	NM_000161.3	ENSP00000419045.2		P30793-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000402

AC:

AN:

249020

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000137

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 1999

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

D;D;D

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.029

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

.;D;.

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.61

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

2.0

M;M;M

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.0

.;N;N

REVEL

Pathogenic

0.70

Sift

Uncertain

0.023

.;D;D

Sift4G

Uncertain

0.016

D;D;D

Polyphen

0.075

B;B;B

Vest4

0.23

MutPred

0.81

Loss of MoRF binding (P = 0.0293);Loss of MoRF binding (P = 0.0293);Loss of MoRF binding (P = 0.0293);

MVP

0.98

MPC

1.2

ClinPred

0.63

GERP RS

4.1

Varity_R

0.42

gMVP

0.91

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over