rs10151500

Variant names:

• chr14-54842875-C-T
• rs10151500
• NM_000161.3:c.*1142G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-54842875-C-T
• chr14-54842875-C-A

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.*1142G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0161 in 501,110 control chromosomes in the GnomAD database, including 572 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (474 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (98 hom.)
• Consequence: GCH1 NM_000161.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.178
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-54842875-C-T is Benign according to our data. Variant chr14-54842875-C-T is described in ClinVar as Benign. ClinVar VariationId is 313370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 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.*1142G>A		3_prime_UTR	Exon 6 of 6	NP_000152.1	P30793-1
	GCH1	NM_001024024.2		c.*196G>A		3_prime_UTR	Exon 7 of 7	NP_001019195.1	P30793-1
	GCH1	NM_001024070.2		c.*192G>A		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.*1142G>A		3_prime_UTR	Exon 6 of 6	ENSP00000419045.2	P30793-1
	GCH1	ENST00000395514.5	TSL:1	c.*196G>A		3_prime_UTR	Exon 7 of 7	ENSP00000378890.1	P30793-1
	GCH1	ENST00000543643.6	TSL:1	c.*192G>A		3_prime_UTR	Exon 7 of 7	ENSP00000444011.2	P30793-4

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6176 AN: 152108 Hom.: 474 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0282

GnomAD4 exome AF: 0.00538 AC: 1878 AN: 348884 Hom.: 98 Cov.: 0 AF XY: 0.00461 AC XY: 829 AN XY: 179936

African (AFR) AF: 0.145 AC: 1377 AN: 9476

American (AMR) AF: 0.0117 AC: 140 AN: 11976

Ashkenazi Jewish (ASJ) AF: 0.000529 AC: 6 AN: 11338

East Asian (EAS) AF: 0.00 AC: 0 AN: 27154

South Asian (SAS) AF: 0.000242 AC: 4 AN: 16522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38548

Middle Eastern (MID) AF: 0.00588 AC: 19 AN: 3232

European-Non Finnish (NFE) AF: 0.000425 AC: 89 AN: 209558

Other (OTH) AF: 0.0115 AC: 243 AN: 21080

GnomAD4 genome AF: 0.0406 AC: 6178 AN: 152226 Hom.: 474 Cov.: 32 AF XY: 0.0395 AC XY: 2942 AN XY: 74428

African (AFR) AF: 0.142 AC: 5871 AN: 41488

American (AMR) AF: 0.0139 AC: 212 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68030

Other (OTH) AF: 0.0279 AC: 59 AN: 2112

Alfa AF: 0.0244 Hom.: 69

Bravo AF: 0.0465

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

ClinVar submissions

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	-0.80
CADD	Benign	1.3
DANN	Benign	0.63
PhyloP100		0.18
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: rs10151500; hg19: chr14-55309593;