chr14-54859275-G-T

Variant names:

• chr14-54859275-G-T
• rs2878169
• NM_000161.3:c.509+406C>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+406C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0768 in 242,470 control chromosomes in the GnomAD database, including 1,126 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 0.073 (640 hom., cov: 32)
  • Exomes 𝑓: 0.083 (486 hom.)
• Consequence: GCH1 NM_000161.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.249
• Publications: 1 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.107 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCH1	NM_000161.3	MANE Select	c.509+406C>A		intron	N/A	NP_000152.1
	GCH1	NM_001024024.2		c.509+406C>A		intron	N/A	NP_001019195.1
	GCH1	NM_001024070.2		c.509+406C>A		intron	N/A	NP_001019241.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCH1	ENST00000491895.7	TSL:1 MANE Select	c.509+406C>A		intron	N/A	ENSP00000419045.2
	GCH1	ENST00000395514.5	TSL:1	c.509+406C>A		intron	N/A	ENSP00000378890.1
	GCH1	ENST00000543643.6	TSL:1	c.509+406C>A		intron	N/A	ENSP00000444011.2

Frequencies

GnomAD3 genomes AF: 0.0730 AC: 11097 AN: 152114 Hom.: 640 Cov.: 32

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0504

Gnomad ASJ AF: 0.0418

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.0602

GnomAD4 exome AF: 0.0835 AC: 7534 AN: 90240 Hom.: 486 Cov.: 0 AF XY: 0.0799 AC XY: 3772 AN XY: 47216

African (AFR) AF: 0.0132 AC: 42 AN: 3170

American (AMR) AF: 0.0431 AC: 194 AN: 4498

Ashkenazi Jewish (ASJ) AF: 0.0491 AC: 104 AN: 2118

East Asian (EAS) AF: 0.00 AC: 0 AN: 5012

South Asian (SAS) AF: 0.0197 AC: 247 AN: 12570

European-Finnish (FIN) AF: 0.142 AC: 560 AN: 3940

Middle Eastern (MID) AF: 0.0193 AC: 7 AN: 362

European-Non Finnish (NFE) AF: 0.111 AC: 5951 AN: 53770

Other (OTH) AF: 0.0894 AC: 429 AN: 4800

GnomAD4 genome AF: 0.0729 AC: 11096 AN: 152230 Hom.: 640 Cov.: 32 AF XY: 0.0740 AC XY: 5505 AN XY: 74432

African (AFR) AF: 0.0163 AC: 678 AN: 41552

American (AMR) AF: 0.0503 AC: 769 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0418 AC: 145 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0180 AC: 87 AN: 4826

European-Finnish (FIN) AF: 0.166 AC: 1755 AN: 10590

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

European-Non Finnish (NFE) AF: 0.109 AC: 7392 AN: 67996

Other (OTH) AF: 0.0596 AC: 126 AN: 2114

Alfa AF: 0.108 Hom.: 168

Bravo AF: 0.0603

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.6
DANN	Benign	0.51
PhyloP100		0.25
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: rs2878169; hg19: chr14-55325993;