rs2878169

Positions:

• chr14-54859275-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.249

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]

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

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
GCH1	NM_000161.3	c.509+406C>A		intron_variant		ENST00000491895.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCH1	ENST00000491895.7	c.509+406C>A		intron_variant		1	NM_000161.3	P1
RNU6ATAC9P	ENST00000516210.1	n.61G>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0730 AC: 11097 AN: 152114 Hom.: 640 Cov.: 32

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.: 0 AF XY: 0.0799 AC XY: 3772 AN XY: 47216

Gnomad4 AFR exome AF: 0.0132

Gnomad4 AMR exome AF: 0.0431

Gnomad4 ASJ exome AF: 0.0491

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0197

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.0894

GnomAD4 genome AF: 0.0729 AC: 11096 AN: 152230 Hom.: 640 Cov.: 32 AF XY: 0.0740 AC XY: 5505 AN XY: 74432

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.0503

Gnomad4 ASJ AF: 0.0418

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0180

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.0596

Alfa AF: 0.111 Hom.: 167

Bravo AF: 0.0603

Asia WGS AF: 0.0130 AC: 46 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
DANN	Benign	0.51

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

Other links and lift over

dbSNP: rs2878169; hg19: chr14-55325993;