chr14-54842834-G-A

Variant names:

• chr14-54842834-G-A
• rs76009965
• NM_000161.3:c.*1183C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000161.3(GCH1):​c.*1183C>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 0.0221 in 416,152 control chromosomes in the GnomAD database, including 753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (650 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (103 hom.)
• Consequence: GCH1 NM_000161.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.331
• Publications: 3 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, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• GTP cyclohydrolase I deficiency

  Inheritance: AD, SD Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• GTP cyclohydrolase I deficiency with hyperphenylalaninemia

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 14-54842834-G-A is Benign according to our data. Variant chr14-54842834-G-A is described in ClinVar as Benign. ClinVar VariationId is 313368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

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.*1183C>T		3_prime_UTR	Exon 6 of 6	NP_000152.1	P30793-1
	GCH1	NM_001024024.2		c.*237C>T		3_prime_UTR	Exon 7 of 7	NP_001019195.1	P30793-1
	GCH1	NM_001024070.2		c.*233C>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.*1183C>T		3_prime_UTR	Exon 6 of 6	ENSP00000419045.2	P30793-1
	GCH1	ENST00000395514.5	TSL:1	c.*237C>T		3_prime_UTR	Exon 7 of 7	ENSP00000378890.1	P30793-1
	GCH1	ENST00000543643.6	TSL:1	c.*233C>T		3_prime_UTR	Exon 7 of 7	ENSP00000444011.2	P30793-4

Frequencies

GnomAD3 genomes AF: 0.0487 AC: 7409 AN: 152096 Hom.: 648 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0320

GnomAD4 exome AF: 0.00668 AC: 1763 AN: 263938 Hom.: 103 Cov.: 0 AF XY: 0.00578 AC XY: 774 AN XY: 133948

African (AFR) AF: 0.171 AC: 1261 AN: 7362

American (AMR) AF: 0.0138 AC: 112 AN: 8120

Ashkenazi Jewish (ASJ) AF: 0.000635 AC: 6 AN: 9448

East Asian (EAS) AF: 0.00 AC: 0 AN: 23282

South Asian (SAS) AF: 0.00 AC: 0 AN: 4146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26930

Middle Eastern (MID) AF: 0.00859 AC: 25 AN: 2910

European-Non Finnish (NFE) AF: 0.000486 AC: 80 AN: 164672

Other (OTH) AF: 0.0163 AC: 279 AN: 17068

GnomAD4 genome AF: 0.0487 AC: 7418 AN: 152214 Hom.: 650 Cov.: 32 AF XY: 0.0474 AC XY: 3529 AN XY: 74420

African (AFR) AF: 0.170 AC: 7056 AN: 41468

American (AMR) AF: 0.0164 AC: 251 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68036

Other (OTH) AF: 0.0317 AC: 67 AN: 2114

Alfa AF: 0.0255 Hom.: 92

Bravo AF: 0.0555

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Dystonia 5 (1)
-	-	1	GTP cyclohydrolase I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.1
DANN	Benign	0.85
PhyloP100		-0.33
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: rs76009965; hg19: chr14-55309552;