4-17501810-C-T

Position:

• chr4-17501810-C-T

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.345G>A​(p.Ser115=) 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:3
• Conservation: PhyloP100: -5.88

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=-0.82).
• BP6: Variant 4-17501810-C-T is Benign according to our data. Variant chr4-17501810-C-T is described in ClinVar as [Benign]. Clinvar id is 348157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-17501810-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
QDPR	NM_000320.3	c.345G>A	p.Ser115=	synonymous_variant	4/7	ENST00000281243.10
QDPR	NM_001306140.2	c.252G>A	p.Ser84=	synonymous_variant	3/6
QDPR	NR_156494.2	n.381G>A		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
QDPR	ENST00000281243.10	c.345G>A	p.Ser115=	synonymous_variant	4/7	1	NM_000320.3	P1

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

GnomAD3 exomes AF: 0.0937 AC: 23547 AN: 251172 Hom.: 3010 AF XY: 0.0847 AC XY: 11494 AN XY: 135734

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 SAS exome AF: 0.0660

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

Gnomad4 AFR exome AF: 0.0829

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.0132

Gnomad4 EAS exome AF: 0.475

Gnomad4 SAS exome AF: 0.0667

Gnomad4 FIN exome AF: 0.0903

Gnomad4 NFE exome AF: 0.0162

Gnomad4 OTH exome AF: 0.0515

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

Gnomad4 AFR AF: 0.0869

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.0193

Gnomad4 EAS AF: 0.437

Gnomad4 SAS AF: 0.0831

Gnomad4 FIN AF: 0.0971

Gnomad4 NFE AF: 0.0182

Gnomad4 OTH AF: 0.0700

Alfa AF: 0.0278 Hom.: 196

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: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 12, 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

Dec 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.75
DANN	Benign	0.35

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