rs12645938

Positions:

• chr4-17504419-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000320.3(QDPR):​c.255C>T​(p.Cys85=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0445 in 1,614,008 control chromosomes in the GnomAD database, including 1,794 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (124 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1670 hom.)
• Consequence: QDPR NM_000320.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.486

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 4-17504419-G-A is Benign according to our data. Variant chr4-17504419-G-A is described in ClinVar as [Benign]. Clinvar id is 348160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-17504419-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.486 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0544 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
QDPR	NM_000320.3	c.255C>T	p.Cys85=	synonymous_variant	3/7	ENST00000281243.10
QDPR	NM_001306140.2	c.162C>T	p.Cys54=	synonymous_variant	2/6
QDPR	NR_156494.2	n.291C>T		non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
QDPR	ENST00000281243.10	c.255C>T	p.Cys85=	synonymous_variant	3/7	1	NM_000320.3	P1

Frequencies

GnomAD3 genomes AF: 0.0352 AC: 5348 AN: 152096 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.00777

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0261

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.0604

Gnomad SAS AF: 0.0412

Gnomad FIN AF: 0.0746

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0466

Gnomad OTH AF: 0.0297

GnomAD3 exomes AF: 0.0405 AC: 10191 AN: 251452 Hom.: 276 AF XY: 0.0412 AC XY: 5596 AN XY: 135896

Gnomad AFR exome AF: 0.00744

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0240

Gnomad EAS exome AF: 0.0571

Gnomad SAS exome AF: 0.0387

Gnomad FIN exome AF: 0.0742

Gnomad NFE exome AF: 0.0458

Gnomad OTH exome AF: 0.0391

GnomAD4 exome AF: 0.0454 AC: 66420 AN: 1461794 Hom.: 1670 Cov.: 32 AF XY: 0.0453 AC XY: 32965 AN XY: 727200

Gnomad4 AFR exome AF: 0.00660

Gnomad4 AMR exome AF: 0.0168

Gnomad4 ASJ exome AF: 0.0241

Gnomad4 EAS exome AF: 0.0727

Gnomad4 SAS exome AF: 0.0393

Gnomad4 FIN exome AF: 0.0756

Gnomad4 NFE exome AF: 0.0466

Gnomad4 OTH exome AF: 0.0431

GnomAD4 genome AF: 0.0351 AC: 5341 AN: 152214 Hom.: 124 Cov.: 32 AF XY: 0.0359 AC XY: 2669 AN XY: 74406

Gnomad4 AFR AF: 0.00775

Gnomad4 AMR AF: 0.0261

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.0599

Gnomad4 SAS AF: 0.0410

Gnomad4 FIN AF: 0.0746

Gnomad4 NFE AF: 0.0465

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0400 Hom.: 119

Bravo AF: 0.0301

Asia WGS AF: 0.0530 AC: 184 AN: 3478

EpiCase AF: 0.0435

EpiControl AF: 0.0433

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dihydropteridine reductase deficiency Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.8
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12645938; hg19: chr4-17506042; COSMIC: COSV55549642;