14-54902522-G-T

Position:

• chr14-54902522-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000161.3(GCH1):​c.142C>A​(p.Gln48Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GCH1 NM_000161.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.51

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain GTP cyclohydrolase 1 (size 249) in uniprot entity GCH1_HUMAN there are 25 pathogenic changes around while only 3 benign (89%) in NM_000161.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20336425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCH1	NM_000161.3	c.142C>A	p.Gln48Lys	missense_variant	1/6	ENST00000491895.7	NP_000152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCH1	ENST00000491895.7	c.142C>A	p.Gln48Lys	missense_variant	1/6	1	NM_000161.3	ENSP00000419045	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	15
DANN	Benign	0.71
DEOGEN2	Benign	0.39	T;T;.;T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.70	.;T;T;.;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.5	L;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.15	.;N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.54	.;T;T;T;T
Sift4G	Benign	0.32	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.19
MutPred		0.27		Gain of glycosylation at Q48 (P = 0.0221);Gain of glycosylation at Q48 (P = 0.0221);Gain of glycosylation at Q48 (P = 0.0221);Gain of glycosylation at Q48 (P = 0.0221);Gain of glycosylation at Q48 (P = 0.0221);
MVP		0.52
MPC		1.3
ClinPred		0.11	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.29
gMVP		0.44

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: rs104894444; hg19: chr14-55369240;