chr15-40764242-G-T

Variant names:

• chr15-40764242-G-T
• rs2016546
• NM_005258.3:c.36+26G>T

Variant summary

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

The NM_005258.3(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 NM_005258.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.379
• Publications: 5 publications found

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]

ENSG00000310466 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005258.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCHFR	NM_005258.3	MANE Select	c.36+26G>T		intron	N/A	NP_005249.1	P30047-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCHFR	ENST00000260447.6	TSL:1 MANE Select	c.36+26G>T		intron	N/A	ENSP00000260447.4	P30047-1
	GCHFR	ENST00000559445.1	TSL:1	c.36+26G>T		intron	N/A	ENSP00000453871.1	P30047-2
	GCHFR	ENST00000561160.1	TSL:3	c.36+26G>T		intron	N/A	ENSP00000454067.1	H0YNM1

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

GnomAD2 exomes AF: 0.0343 AC: 5173 AN: 150960 AF XY: 0.0322

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 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

African (AFR) AF: 0.255 AC: 7814 AN: 30622

American (AMR) AF: 0.0350 AC: 1252 AN: 35774

Ashkenazi Jewish (ASJ) AF: 0.0272 AC: 674 AN: 24762

East Asian (EAS) AF: 0.0243 AC: 861 AN: 35408

South Asian (SAS) AF: 0.0545 AC: 4289 AN: 78686

European-Finnish (FIN) AF: 0.00111 AC: 53 AN: 47614

Middle Eastern (MID) AF: 0.0429 AC: 242 AN: 5640

European-Non Finnish (NFE) AF: 0.0109 AC: 11696 AN: 1077240

Other (OTH) AF: 0.0348 AC: 2005 AN: 57682

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

African (AFR) AF: 0.250 AC: 10384 AN: 41512

American (AMR) AF: 0.0462 AC: 707 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0285 AC: 99 AN: 3472

East Asian (EAS) AF: 0.0241 AC: 125 AN: 5180

South Asian (SAS) AF: 0.0663 AC: 320 AN: 4824

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10616

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 789 AN: 68014

Other (OTH) AF: 0.0686 AC: 145 AN: 2114

Alfa AF: 0.0361 Hom.: 403

Bravo AF: 0.0927

Asia WGS AF: 0.0610 AC: 213 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.9
DANN	Benign	0.60
PhyloP100		-0.38
PromoterAI		-0.0092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2016546; hg19: chr15-41056440;