4-17486728-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000320.3(QDPR):c.*403A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0949 in 237,910 control chromosomes in the GnomAD database, including 2,632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1873 hom., cov: 33)
  • Exomes 𝑓: 0.067 (759 hom.)
• Consequence: QDPR NM_000320.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.100

Genes affected

QDPR (HGNC:9752): (quinoid dihydropteridine reductase) This gene encodes the enzyme dihydropteridine reductase, which catalyzes the NADH-mediated reduction of quinonoid dihydrobiopterin. This enzyme is an essential component of the pterin-dependent aromatic amino acid hydroxylating systems. Mutations in this gene resulting in QDPR deficiency include aberrant splicing, amino acid substitutions, insertions, or premature terminations. Dihydropteridine reductase deficiency presents as atypical phenylketonuria due to insufficient production of biopterin, a cofactor for phenylalanine hydroxylase. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-17486728-T-C is Benign according to our data. Variant chr4-17486728-T-C is described in ClinVar as [Benign]. Clinvar id is 348145.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
QDPR	NM_000320.3	c.*403A>G		3_prime_UTR_variant	7/7	ENST00000281243.10
QDPR	NM_001306140.2	c.*403A>G		3_prime_UTR_variant	6/6
QDPR	NR_156494.2	n.1065A>G		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
QDPR	ENST00000281243.10	c.*403A>G		3_prime_UTR_variant	7/7	1	NM_000320.3	P1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16782 AN: 152028 Hom.: 1863 Cov.: 33

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.0851

Gnomad FIN AF: 0.0961

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0961

GnomAD4 exome AF: 0.0672 AC: 5762 AN: 85764 Hom.: 759 Cov.: 0 AF XY: 0.0672 AC XY: 3011 AN XY: 44828

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.164

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.441

Gnomad4 SAS exome AF: 0.0606

Gnomad4 FIN exome AF: 0.0810

Gnomad4 NFE exome AF: 0.0154

Gnomad4 OTH exome AF: 0.0528

GnomAD4 genome AF: 0.111 AC: 16824 AN: 152146 Hom.: 1873 Cov.: 33 AF XY: 0.119 AC XY: 8821 AN XY: 74374

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.440

Gnomad4 SAS AF: 0.0841

Gnomad4 FIN AF: 0.0961

Gnomad4 NFE AF: 0.0187

Gnomad4 OTH AF: 0.0956

Alfa AF: 0.0375 Hom.: 468

Bravo AF: 0.122

Asia WGS AF: 0.240 AC: 832 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dihydropteridine reductase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	5.8
Dann	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs1049600; hg19: chr4-17488351;