rs12645938

Variant names:

• chr4-17504419-G-A
• rs12645938
• NM_000320.3:c.255C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000320.3(QDPR):​c.255C>T​(p.Cys85Cys) 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:4
• Conservation: PhyloP100: 0.486
• Publications: 8 publications found

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]

QDPR Gene-Disease associations (from GenCC):

• dihydropteridine reductase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.108).
• BP6: Variant 4-17504419-G-A is Benign according to our data. Variant chr4-17504419-G-A is described in ClinVar as Benign. ClinVar VariationId is 348160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
QDPR	NM_000320.3	c.255C>T	p.Cys85Cys	synonymous_variant	Exon 3 of 7	ENST00000281243.10	NP_000311.2
QDPR	NM_001306140.2	c.162C>T	p.Cys54Cys	synonymous_variant	Exon 2 of 6		NP_001293069.1
QDPR	NR_156494.2	n.291C>T		non_coding_transcript_exon_variant	Exon 3 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
QDPR	ENST00000281243.10	c.255C>T	p.Cys85Cys	synonymous_variant	Exon 3 of 7	1	NM_000320.3	ENSP00000281243.5

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

GnomAD2 exomes AF: 0.0405 AC: 10191 AN: 251452 AF XY: 0.0412

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 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

African (AFR) AF: 0.00660 AC: 221 AN: 33480

American (AMR) AF: 0.0168 AC: 752 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0241 AC: 629 AN: 26136

East Asian (EAS) AF: 0.0727 AC: 2888 AN: 39698

South Asian (SAS) AF: 0.0393 AC: 3386 AN: 86254

European-Finnish (FIN) AF: 0.0756 AC: 4036 AN: 53416

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5768

European-Non Finnish (NFE) AF: 0.0466 AC: 51809 AN: 1111922

Other (OTH) AF: 0.0431 AC: 2601 AN: 60396

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

African (AFR) AF: 0.00775 AC: 322 AN: 41542

American (AMR) AF: 0.0261 AC: 399 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3468

East Asian (EAS) AF: 0.0599 AC: 310 AN: 5174

South Asian (SAS) AF: 0.0410 AC: 198 AN: 4830

European-Finnish (FIN) AF: 0.0746 AC: 789 AN: 10582

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0465 AC: 3163 AN: 68002

Other (OTH) AF: 0.0298 AC: 63 AN: 2112

Alfa AF: 0.0401 Hom.: 140

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dihydropteridine reductase deficiency Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Nov 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.8
DANN	Benign	0.55
PhyloP100		0.49
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12645938; hg19: chr4-17506042; COSMIC: COSV55549642;