rs2518608

chr4-17511959-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000320.3(QDPR):c.96C>T(p.Ala32=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,610,798 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (5 hom., cov: 32)
  • Exomes 𝑓: 0.012 (151 hom.)
• Consequence: QDPR NM_000320.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.78

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 4-17511959-G-A is Benign according to our data. Variant chr4-17511959-G-A is described in ClinVar as [Benign]. Clinvar id is 286391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-17511959-G-A is described in Lovd as [Benign]. Variant chr4-17511959-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00805 (1224/152060) while in subpopulation SAS AF= 0.0133 (64/4818). AF 95% confidence interval is 0.0124. There are 5 homozygotes in gnomad4. There are 571 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
QDPR	NM_000320.3	c.96C>T	p.Ala32=	synonymous_variant	1/7	ENST00000281243.10
QDPR	NM_001306140.2	c.96C>T	p.Ala32=	synonymous_variant	1/6
QDPR	NR_156494.2	n.132C>T		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
QDPR	ENST00000281243.10	c.96C>T	p.Ala32=	synonymous_variant	1/7	1	NM_000320.3	P1

Frequencies

GnomAD3 genomes AF: 0.00808 AC: 1228 AN: 151946 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00463

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00865

GnomAD3 exomes AF: 0.0109 AC: 2582 AN: 236828 Hom.: 23 AF XY: 0.0119 AC XY: 1549 AN XY: 130558

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.00346

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.0173

Gnomad FIN exome AF: 0.00601

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0122 AC: 17730 AN: 1458738 Hom.: 151 Cov.: 32 AF XY: 0.0125 AC XY: 9054 AN XY: 725738

Gnomad4 AFR exome AF: 0.00165

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.0150

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0184

Gnomad4 FIN exome AF: 0.00658

Gnomad4 NFE exome AF: 0.0130

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00805 AC: 1224 AN: 152060 Hom.: 5 Cov.: 32 AF XY: 0.00768 AC XY: 571 AN XY: 74356

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.00463

Gnomad4 NFE AF: 0.0131

Gnomad4 OTH AF: 0.00856

Alfa AF: 0.0127 Hom.: 8

Bravo AF: 0.00737

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0148

EpiControl AF: 0.0153

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dihydropteridine reductase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 29, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	14
Dann	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs2518608; hg19: chr4-17513582;