14-54842887-G-A

Variant names:

• chr14-54842887-G-A
• rs543818323
• NM_000161.3:c.*1130C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000161.3(GCH1):​c.*1130C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000024 in 416,990 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: GCH1 NM_000161.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.387
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

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.*1130C>T		3_prime_UTR	Exon 6 of 6	NP_000152.1	P30793-1
	GCH1	NM_001024024.2		c.*184C>T		3_prime_UTR	Exon 7 of 7	NP_001019195.1	P30793-1
	GCH1	NM_001024070.2		c.*180C>T		3_prime_UTR	Exon 7 of 7	NP_001019241.1	P30793-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCH1	ENST00000491895.7	TSL:1 MANE Select	c.*1130C>T		3_prime_UTR	Exon 6 of 6	ENSP00000419045.2	P30793-1
	GCH1	ENST00000395514.5	TSL:1	c.*184C>T		3_prime_UTR	Exon 7 of 7	ENSP00000378890.1	P30793-1
	GCH1	ENST00000543643.6	TSL:1	c.*180C>T		3_prime_UTR	Exon 7 of 7	ENSP00000444011.2	P30793-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000240 AC: 1 AN: 416990 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 218382

African (AFR) AF: 0.00 AC: 0 AN: 11300

American (AMR) AF: 0.00 AC: 0 AN: 16008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13002

East Asian (EAS) AF: 0.00 AC: 0 AN: 29714

South Asian (SAS) AF: 0.00 AC: 0 AN: 29938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3514

European-Non Finnish (NFE) AF: 0.00000405 AC: 1 AN: 246842

Other (OTH) AF: 0.00 AC: 0 AN: 24310

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.9
DANN	Benign	0.66
PhyloP100		0.39

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: rs543818323; hg19: chr14-55309605;