14-54842960-G-GAT

Position:

• chr14-54842960-G-GAT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000161.3(GCH1):​c.*1056_*1057insAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 723,872 control chromosomes in the GnomAD database, including 647 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (466 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (181 hom.)
• Consequence: GCH1 NM_000161.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.760

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 14-54842960-G-GAT is Benign according to our data. Variant chr14-54842960-G-GAT is described in ClinVar as [Benign]. Clinvar id is 313373.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCH1	NM_000161.3	c.*1056_*1057insAT		3_prime_UTR_variant	6/6	ENST00000491895.7	NP_000152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895	c.*1056_*1057insAT		3_prime_UTR_variant	6/6	1	NM_000161.3	ENSP00000419045.2

Frequencies

GnomAD3 genomes AF: 0.0405 AC: 6164 AN: 152090 Hom.: 466 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0283

GnomAD4 exome AF: 0.00549 AC: 3141 AN: 571664 Hom.: 181 Cov.: 5 AF XY: 0.00442 AC XY: 1367 AN XY: 309130

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.00935

Gnomad4 ASJ exome AF: 0.000521

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000295

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000432

Gnomad4 OTH exome AF: 0.0105

GnomAD4 genome AF: 0.0405 AC: 6166 AN: 152208 Hom.: 466 Cov.: 32 AF XY: 0.0395 AC XY: 2942 AN XY: 74434

Gnomad4 AFR AF: 0.141

Gnomad4 AMR AF: 0.0138

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0280

Alfa AF: 0.0312 Hom.: 31

Bravo AF: 0.0464

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GTP cyclohydrolase I deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dopa-responsive dystonia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144676716; hg19: chr14-55309678;