NM_000320.3:c.345G>A

Variant names:

• chr4-17501810-C-T
• rs3733570
• NM_000320.3:c.345G>A

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.345G>A​(p.Ser115Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 1,614,044 control chromosomes in the GnomAD database, including 7,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S115S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.070 (932 hom., cov: 32)
  • Exomes 𝑓: 0.043 (6533 hom.)
• Consequence: QDPR NM_000320.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -5.88
• Publications: 18 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=0.029).
• BP6: Variant 4-17501810-C-T is Benign according to our data. Variant chr4-17501810-C-T is described in ClinVar as Benign. ClinVar VariationId is 348157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.88 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
QDPR	NM_000320.3	c.345G>A	p.Ser115Ser	synonymous_variant	Exon 4 of 7	ENST00000281243.10	NP_000311.2
QDPR	NM_001306140.2	c.252G>A	p.Ser84Ser	synonymous_variant	Exon 3 of 6		NP_001293069.1
QDPR	NR_156494.2	n.381G>A		non_coding_transcript_exon_variant	Exon 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
QDPR	ENST00000281243.10	c.345G>A	p.Ser115Ser	synonymous_variant	Exon 4 of 7	1	NM_000320.3	ENSP00000281243.5

Frequencies

GnomAD3 genomes AF: 0.0704 AC: 10702 AN: 152084 Hom.: 932 Cov.: 32

Gnomad AFR AF: 0.0869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0193

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.0842

Gnomad FIN AF: 0.0971

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0182

Gnomad OTH AF: 0.0703

GnomAD2 exomes AF: 0.0937 AC: 23547 AN: 251172 AF XY: 0.0847

Gnomad AFR exome AF: 0.0862

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.0135

Gnomad EAS exome AF: 0.444

Gnomad FIN exome AF: 0.0936

Gnomad NFE exome AF: 0.0192

Gnomad OTH exome AF: 0.0664

GnomAD4 exome AF: 0.0429 AC: 62663 AN: 1461842 Hom.: 6533 Cov.: 36 AF XY: 0.0425 AC XY: 30902 AN XY: 727216

African (AFR) AF: 0.0829 AC: 2777 AN: 33480

American (AMR) AF: 0.197 AC: 8804 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 345 AN: 26134

East Asian (EAS) AF: 0.475 AC: 18860 AN: 39700

South Asian (SAS) AF: 0.0667 AC: 5751 AN: 86252

European-Finnish (FIN) AF: 0.0903 AC: 4822 AN: 53406

Middle Eastern (MID) AF: 0.0392 AC: 226 AN: 5766

European-Non Finnish (NFE) AF: 0.0162 AC: 17965 AN: 1111988

Other (OTH) AF: 0.0515 AC: 3113 AN: 60392

GnomAD4 genome AF: 0.0703 AC: 10707 AN: 152202 Hom.: 932 Cov.: 32 AF XY: 0.0789 AC XY: 5871 AN XY: 74408

African (AFR) AF: 0.0869 AC: 3609 AN: 41522

American (AMR) AF: 0.128 AC: 1952 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0193 AC: 67 AN: 3472

East Asian (EAS) AF: 0.437 AC: 2257 AN: 5162

South Asian (SAS) AF: 0.0831 AC: 400 AN: 4816

European-Finnish (FIN) AF: 0.0971 AC: 1028 AN: 10592

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0182 AC: 1239 AN: 68022

Other (OTH) AF: 0.0700 AC: 148 AN: 2114

Alfa AF: 0.0317 Hom.: 302

Bravo AF: 0.0761

Asia WGS AF: 0.223 AC: 772 AN: 3478

EpiCase AF: 0.0169

EpiControl AF: 0.0179

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dihydropteridine reductase deficiency Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.75
DANN	Benign	0.35
PhyloP100		-5.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3733570; hg19: chr4-17503433; COSMIC: COSV55550112;