rs7147286

Variant names:

• chr14-54891947-G-A
• rs7147286
• NM_000161.3:c.343+10374C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-54891947-G-A
• chr14-54891947-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000161.3(GCH1):​c.343+10374C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 152,010 control chromosomes in the GnomAD database, including 15,575 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 0.43 (15575 hom., cov: 32)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.86
• Publications: 9 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.648 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCH1	NM_000161.3	c.343+10374C>T		intron_variant	Intron 1 of 5	ENST00000491895.7	NP_000152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7	c.343+10374C>T		intron_variant	Intron 1 of 5	1	NM_000161.3	ENSP00000419045.2

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64915 AN: 151892 Hom.: 15529 Cov.: 32

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.375

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.428 AC: 65032 AN: 152010 Hom.: 15575 Cov.: 32 AF XY: 0.429 AC XY: 31884 AN XY: 74286

African (AFR) AF: 0.654 AC: 27144 AN: 41474

American (AMR) AF: 0.351 AC: 5355 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 908 AN: 3468

East Asian (EAS) AF: 0.325 AC: 1682 AN: 5176

South Asian (SAS) AF: 0.399 AC: 1919 AN: 4810

European-Finnish (FIN) AF: 0.407 AC: 4277 AN: 10512

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22418 AN: 67988

Other (OTH) AF: 0.380 AC: 800 AN: 2108

Alfa AF: 0.358 Hom.: 28529

Bravo AF: 0.431

Asia WGS AF: 0.393 AC: 1366 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.17
DANN	Benign	0.40
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7147286; hg19: chr14-55358665;