chr15-40764242-G-T

Position:

• chr15-40764242-G-T

Variant summary

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

The ENST00000260447.6(GCHFR):​c.36+26G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,545,674 control chromosomes in the GnomAD database, including 2,743 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 0.083 (1342 hom., cov: 33)
  • Exomes 𝑓: 0.021 (1401 hom.)
• Consequence: GCHFR ENST00000260447.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.379

Genes affected

GCHFR (HGNC:4194): (GTP cyclohydrolase I feedback regulator) GTP cyclohydrolase I feedback regulatory protein binds to and mediates tetrahydrobiopterin inhibition of GTP cyclohydrolase I. The regulatory protein, GCHFR, consists of a homodimer. It is postulated that GCHFR may play a role in regulating phenylalanine metabolism in the liver and in the production of biogenic amine neurotransmitters and nitric oxide. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCHFR	NM_005258.3	c.36+26G>T		intron_variant		ENST00000260447.6	NP_005249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCHFR	ENST00000260447.6	c.36+26G>T		intron_variant		1	NM_005258.3	ENSP00000260447	P1
GCHFR	ENST00000559445.1	c.36+26G>T		intron_variant		1		ENSP00000453871
GCHFR	ENST00000558670.1	c.36+26G>T		intron_variant		3		ENSP00000477896
GCHFR	ENST00000561160.1	c.36+26G>T		intron_variant		3		ENSP00000454067

Frequencies

GnomAD3 genomes AF: 0.0826 AC: 12572 AN: 152128 Hom.: 1335 Cov.: 33

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0462

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.0669

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.0693

GnomAD3 exomes AF: 0.0343 AC: 5173 AN: 150960 Hom.: 333 AF XY: 0.0322 AC XY: 2616 AN XY: 81364

Gnomad AFR exome AF: 0.248

Gnomad AMR exome AF: 0.0314

Gnomad ASJ exome AF: 0.0247

Gnomad EAS exome AF: 0.0197

Gnomad SAS exome AF: 0.0562

Gnomad FIN exome AF: 0.00123

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0309

GnomAD4 exome AF: 0.0207 AC: 28886 AN: 1393428 Hom.: 1401 Cov.: 29 AF XY: 0.0211 AC XY: 14502 AN XY: 687584

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.0350

Gnomad4 ASJ exome AF: 0.0272

Gnomad4 EAS exome AF: 0.0243

Gnomad4 SAS exome AF: 0.0545

Gnomad4 FIN exome AF: 0.00111

Gnomad4 NFE exome AF: 0.0109

Gnomad4 OTH exome AF: 0.0348

GnomAD4 genome AF: 0.0828 AC: 12599 AN: 152246 Hom.: 1342 Cov.: 33 AF XY: 0.0794 AC XY: 5911 AN XY: 74458

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.0462

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.0241

Gnomad4 SAS AF: 0.0663

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.0116

Gnomad4 OTH AF: 0.0686

Alfa AF: 0.0247 Hom.: 146

Bravo AF: 0.0927

Asia WGS AF: 0.0610 AC: 213 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.9
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2016546; hg19: chr15-41056440;