14-54842552-A-AAT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000161.3(GCH1):c.*1464_*1465insAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 153,894 control chromosomes in the GnomAD database, including 38 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (37 hom., cov: 32)
  • Exomes 𝑓: 0.015 (1 hom.)
• Consequence: GCH1 NM_000161.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0760

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 Benign. Variant got -10 ACMG points.

• BP6: Variant 14-54842552-A-AAT is Benign according to our data. Variant chr14-54842552-A-AAT is described in ClinVar as [Likely_benign]. Clinvar id is 313364.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0163 (2483/152272) while in subpopulation SAS AF= 0.0482 (232/4814). AF 95% confidence interval is 0.0431. There are 37 homozygotes in gnomad4. There are 1342 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 38 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCH1	NM_000161.3	c.*1464_*1465insAT		3_prime_UTR_variant	6/6	ENST00000491895.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCH1	ENST00000491895.7	c.*1464_*1465insAT		3_prime_UTR_variant	6/6	1	NM_000161.3	P1

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2485 AN: 152154 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.00924

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0486

Gnomad FIN AF: 0.0472

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0182

GnomAD4 exome AF: 0.0154 AC: 25 AN: 1622 Hom.: 1 Cov.: 0 AF XY: 0.0169 AC XY: 15 AN XY: 886

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0417

Gnomad4 FIN exome AF: 0.0282

Gnomad4 NFE exome AF: 0.0142

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.0163 AC: 2483 AN: 152272 Hom.: 37 Cov.: 32 AF XY: 0.0180 AC XY: 1342 AN XY: 74470

Gnomad4 AFR AF: 0.00291

Gnomad4 AMR AF: 0.0159

Gnomad4 ASJ AF: 0.00924

Gnomad4 EAS AF: 0.00250

Gnomad4 SAS AF: 0.0482

Gnomad4 FIN AF: 0.0472

Gnomad4 NFE AF: 0.0187

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0211 Hom.: 3

Bravo AF: 0.0134

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

GTP cyclohydrolase I deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dopa-responsive dystonia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55885280; hg19: chr14-55309270;