14-54859144-A-T

Variant names:

• chr14-54859144-A-T
• rs12589758
• NM_000161.3:c.509+537T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000161.3(GCH1):​c.509+537T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 163,014 control chromosomes in the GnomAD database, including 3,869 homozygotes. 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: 𝑓 0.22 (3678 hom., cov: 32)
  • Exomes 𝑓: 0.17 (191 hom.)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.741
• Publications: 4 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]

RNU6ATAC9P (HGNC:46908): (RNA, U6atac small nuclear 9, pseudogene)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.343 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.509+537T>A		intron	N/A	NP_000152.1	P30793-1
	GCH1	NM_001024024.2		c.509+537T>A		intron	N/A	NP_001019195.1	P30793-1
	GCH1	NM_001024070.2		c.509+537T>A		intron	N/A	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.509+537T>A		intron	N/A	ENSP00000419045.2	P30793-1
	GCH1	ENST00000395514.5	TSL:1	c.509+537T>A		intron	N/A	ENSP00000378890.1	P30793-1
	GCH1	ENST00000543643.6	TSL:1	c.509+537T>A		intron	N/A	ENSP00000444011.2	P30793-4

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32721 AN: 152098 Hom.: 3674 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.146

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.215

GnomAD4 exome AF: 0.169 AC: 1826 AN: 10798 Hom.: 191 AF XY: 0.169 AC XY: 933 AN XY: 5518

African (AFR) AF: 0.102 AC: 13 AN: 128

American (AMR) AF: 0.245 AC: 466 AN: 1902

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 7 AN: 96

East Asian (EAS) AF: 0.256 AC: 105 AN: 410

South Asian (SAS) AF: 0.0849 AC: 89 AN: 1048

European-Finnish (FIN) AF: 0.162 AC: 37 AN: 228

Middle Eastern (MID) AF: 0.0417 AC: 1 AN: 24

European-Non Finnish (NFE) AF: 0.157 AC: 1007 AN: 6408

Other (OTH) AF: 0.182 AC: 101 AN: 554

GnomAD4 genome AF: 0.215 AC: 32755 AN: 152216 Hom.: 3678 Cov.: 32 AF XY: 0.218 AC XY: 16220 AN XY: 74420

African (AFR) AF: 0.196 AC: 8154 AN: 41534

American (AMR) AF: 0.294 AC: 4492 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.146 AC: 507 AN: 3468

East Asian (EAS) AF: 0.356 AC: 1843 AN: 5172

South Asian (SAS) AF: 0.132 AC: 638 AN: 4824

European-Finnish (FIN) AF: 0.245 AC: 2600 AN: 10596

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13762 AN: 68004

Other (OTH) AF: 0.213 AC: 450 AN: 2116

Alfa AF: 0.199 Hom.: 419

Bravo AF: 0.221

Asia WGS AF: 0.200 AC: 696 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.8
DANN	Benign	0.75
PhyloP100		0.74
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs12589758;

hg19: chr14-55325862;