Genetic Variant GCHFR:c.36+26G>T (chr15-40764242-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.379

Publications

5 publications found

Variant links:

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]

GCHFR links:

ENSG00000310466 (HGNC:):

ENSG00000310466 links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCHFR	NM_005258.3 link	c.36+26G>T		intron_variant	Intron 1 of 2	ENST00000260447.6	NP_005249.1	P30047-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCHFR	ENST00000260447.6 link	c.36+26G>T		intron_variant	Intron 1 of 2	1	NM_005258.3	ENSP00000260447.4		P30047-1

Frequencies

GnomAD3 genomes

AF:

0.0826

AC:

12572

AN:

152128

Hom.:

1335

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0211

AC XY:

14502

AN XY:

687584

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

1244

2488

3732

4976

6220

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0828

AC:

12599

AN:

152246

Hom.:

1342

Cov.:

AF XY:

0.0794

AC XY:

5911

AN XY:

74458

show subpopulations

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:

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:

AN:

10616

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0116

AC:

789

AN:

68014

Other (OTH)

AF:

0.0686

AC:

145

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

510

1020

1529

2039

2549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.9

(source)

DANN

Benign

0.60

PhyloP100

-0.38

PromoterAI

-0.0092

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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15-40764242-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over