14-54842538-C-A

Variant names:

• chr14-54842538-C-A
• rs533240612
• NM_000161.3:c.*1479G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000161.3(GCH1):​c.*1479G>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 0.000457 in 153,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (0 hom.)
• Consequence: GCH1 NM_000161.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.37
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 14-54842538-C-A is Benign according to our data. Variant chr14-54842538-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 313362.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000454 (69/152148) while in subpopulation SAS AF = 0.00479 (23/4800). AF 95% confidence interval is 0.00327. There are 1 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.*1479G>T		3_prime_UTR	Exon 6 of 6	NP_000152.1	P30793-1
	GCH1	NM_001024024.2		c.*533G>T		3_prime_UTR	Exon 7 of 7	NP_001019195.1	P30793-1
	GCH1	NM_001024070.2		c.*529G>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.*1479G>T		3_prime_UTR	Exon 6 of 6	ENSP00000419045.2	P30793-1
	GCH1	ENST00000395514.5	TSL:1	c.*533G>T		3_prime_UTR	Exon 7 of 7	ENSP00000378890.1	P30793-1
	GCH1	ENST00000543643.6	TSL:1	c.*529G>T		3_prime_UTR	Exon 7 of 7	ENSP00000444011.2	P30793-4

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 152028 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00479

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000990 AC: 1 AN: 1010 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 582

African (AFR) AF: 0.00 AC: 0 AN: 36

American (AMR) AF: 0.00 AC: 0 AN: 24

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26

East Asian (EAS) AF: 0.00 AC: 0 AN: 18

South Asian (SAS) AF: 0.00 AC: 0 AN: 10

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00224 AC: 1 AN: 446

Other (OTH) AF: 0.00 AC: 0 AN: 54

GnomAD4 genome AF: 0.000454 AC: 69 AN: 152148 Hom.: 1 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74374

African (AFR) AF: 0.0000723 AC: 3 AN: 41520

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

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

South Asian (SAS) AF: 0.00479 AC: 23 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68004

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000314

Asia WGS AF: 0.00173 AC: 6 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Dopa-responsive dystonia (1)
-	-	1	GTP cyclohydrolase I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.049
DANN	Benign	0.16
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

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: rs533240612; hg19: chr14-55309256;