rs2315248

Positions:

• chr4-17504541-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000320.3(QDPR):​c.199-66C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,271,074 control chromosomes in the GnomAD database, including 19,142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2080 hom., cov: 33)
  • Exomes 𝑓: 0.17 (17062 hom.)
• Consequence: QDPR NM_000320.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.897

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-17504541-G-A is Benign according to our data. Variant chr4-17504541-G-A is described in ClinVar as [Benign]. Clinvar id is 1288544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
QDPR	NM_000320.3	c.199-66C>T		intron_variant		ENST00000281243.10	NP_000311.2
QDPR	NM_001306140.2	c.106-66C>T		intron_variant			NP_001293069.1
QDPR	NR_156494.2	n.235-66C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
QDPR	ENST00000281243.10	c.199-66C>T		intron_variant		1	NM_000320.3	ENSP00000281243	P1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24225 AN: 152020 Hom.: 2083 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.181

GnomAD4 exome AF: 0.172 AC: 192724 AN: 1118936 Hom.: 17062 AF XY: 0.170 AC XY: 97468 AN XY: 572356

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.220

Gnomad4 ASJ exome AF: 0.209

Gnomad4 EAS exome AF: 0.0929

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.181

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.159 AC: 24241 AN: 152138 Hom.: 2080 Cov.: 33 AF XY: 0.157 AC XY: 11650 AN XY: 74366

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.106

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.179

Gnomad4 OTH AF: 0.181

Alfa AF: 0.162 Hom.: 346

Bravo AF: 0.167

Asia WGS AF: 0.126 AC: 438 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.6
DANN	Benign	0.73

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: rs2315248; hg19: chr4-17506164; COSMIC: COSV55549900;