rs41298442

Variant names:

• chr14-54844099-T-C
• rs41298442
• NM_000161.3:c.671A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-54844099-T-C
• chr14-54844099-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PP2 PP5 BP4 BS1_Supporting

The NM_000161.3(GCH1):​c.671A>G​(p.Lys224Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000375 in 1,614,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K224T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: GCH1 NM_000161.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13 U:4
• Conservation: PhyloP100: 4.22
• Publications: 28 publications found

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 Gene-Disease associations (from GenCC):

• dystonia 5

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• GTP cyclohydrolase I deficiency with hyperphenylalaninemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• GTP cyclohydrolase I deficiency

  Inheritance: SD, AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000161.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 30 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 1.5191 (below the threshold of 3.09). Trascript score misZ: 0.62455 (below the threshold of 3.09). GenCC associations: The gene is linked to GTP cyclohydrolase I deficiency, dystonia 5, GTP cyclohydrolase I deficiency with hyperphenylalaninemia.
• PP5: Variant 14-54844099-T-C is Pathogenic according to our data. Variant chr14-54844099-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 9283.
• BP4: Computational evidence support a benign effect (MetaRNN=0.064124316). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000394 (60/152344) while in subpopulation AMR AF = 0.00163 (25/15304). AF 95% confidence interval is 0.00113. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000161.3. 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
	GCH1	NM_000161.3	MANE Select	c.671A>G	p.Lys224Arg	missense	Exon 6 of 6	NP_000152.1	P30793-1
	GCH1	NM_001024024.2		c.671A>G	p.Lys224Arg	missense	Exon 6 of 7	NP_001019195.1	P30793-1
	GCH1	NM_001424105.1		c.377A>G	p.Lys126Arg	missense	Exon 6 of 6	NP_001411034.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCH1	ENST00000491895.7	TSL:1 MANE Select	c.671A>G	p.Lys224Arg	missense	Exon 6 of 6	ENSP00000419045.2	P30793-1
	GCH1	ENST00000395514.5	TSL:1	c.671A>G	p.Lys224Arg	missense	Exon 6 of 7	ENSP00000378890.1	P30793-1
	GCH1	ENST00000543643.6	TSL:1	c.627-230A>G		intron	N/A	ENSP00000444011.2	P30793-4

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000386 AC: 96 AN: 248968 AF XY: 0.000386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000521

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000374 AC: 546 AN: 1461784 Hom.: 0 Cov.: 31 AF XY: 0.000375 AC XY: 273 AN XY: 727198

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.000760 AC: 34 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000435 AC: 484 AN: 1111912

Other (OTH) AF: 0.000364 AC: 22 AN: 60392

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152344 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74502

African (AFR) AF: 0.0000481 AC: 2 AN: 41572

American (AMR) AF: 0.00163 AC: 25 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000420 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.000654

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	1	-	Dystonia 5 (4)
2	2	-	not provided (4)
2	-	-	Dystonia 5;CN305333:GTP cyclohydrolase I deficiency with hyperphenylalaninemia (2)
2	-	-	GTP cyclohydrolase I deficiency (2)
1	-	-	Dopa-responsive dystonia (1)
1	-	-	Dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive (1)
1	-	-	GTP cyclohydrolase I deficiency with hyperphenylalaninemia (1)
1	-	-	GTP cyclohydrolase I deficiency;C1851920:Dystonia 5 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.0090	T
BayesDel_noAF	Uncertain	0.13
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.064	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.94	L
PhyloP100		4.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.54
Sift	Benign	0.45	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.62
MVP		0.99
MPC		0.86
ClinPred		0.037	T
GERP RS		2.3
Varity_R		0.16
gMVP		0.78
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41298442; hg19: chr14-55310817;