4-17501759-C-T

Variant names:

• chr4-17501759-C-T
• rs2597775
• NM_000320.3:c.396G>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.396G>A​(p.Leu132Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,613,742 control chromosomes in the GnomAD database, including 84,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6736 hom., cov: 32)
  • Exomes 𝑓: 0.32 (78249 hom.)
• Consequence: QDPR NM_000320.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.19
• Publications: 20 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 (BayesDel_noAF=-0.3).
• BP6: Variant 4-17501759-C-T is Benign according to our data. Variant chr4-17501759-C-T is described in ClinVar as Benign. ClinVar VariationId is 255819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000320.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QDPR	NM_000320.3	MANE Select	c.396G>A	p.Leu132Leu	synonymous	Exon 4 of 7	NP_000311.2
	QDPR	NM_001306140.2		c.303G>A	p.Leu101Leu	synonymous	Exon 3 of 6	NP_001293069.1
	QDPR	NR_156494.2		n.432G>A		non_coding_transcript_exon	Exon 4 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QDPR	ENST00000281243.10	TSL:1 MANE Select	c.396G>A	p.Leu132Leu	synonymous	Exon 4 of 7	ENSP00000281243.5
	QDPR	ENST00000910937.1		c.471G>A	p.Leu157Leu	synonymous	Exon 4 of 7	ENSP00000580996.1
	QDPR	ENST00000910936.1		c.444G>A	p.Leu148Leu	synonymous	Exon 5 of 8	ENSP00000580995.1

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43314 AN: 151996 Hom.: 6730 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.299

GnomAD2 exomes AF: 0.281 AC: 70687 AN: 251142 AF XY: 0.296

Gnomad AFR exome AF: 0.239

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.324

Gnomad EAS exome AF: 0.00903

Gnomad FIN exome AF: 0.299

Gnomad NFE exome AF: 0.333

Gnomad OTH exome AF: 0.302

GnomAD4 exome AF: 0.320 AC: 468272 AN: 1461628 Hom.: 78249 Cov.: 45 AF XY: 0.324 AC XY: 235762 AN XY: 727108

African (AFR) AF: 0.239 AC: 8012 AN: 33476

American (AMR) AF: 0.160 AC: 7161 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 8443 AN: 26134

East Asian (EAS) AF: 0.0190 AC: 754 AN: 39700

South Asian (SAS) AF: 0.390 AC: 33624 AN: 86250

European-Finnish (FIN) AF: 0.298 AC: 15879 AN: 53366

Middle Eastern (MID) AF: 0.422 AC: 2428 AN: 5756

European-Non Finnish (NFE) AF: 0.336 AC: 373091 AN: 1111840

Other (OTH) AF: 0.313 AC: 18880 AN: 60388

GnomAD4 genome AF: 0.285 AC: 43344 AN: 152114 Hom.: 6736 Cov.: 32 AF XY: 0.282 AC XY: 20998 AN XY: 74348

African (AFR) AF: 0.234 AC: 9695 AN: 41500

American (AMR) AF: 0.239 AC: 3647 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1086 AN: 3470

East Asian (EAS) AF: 0.0187 AC: 97 AN: 5178

South Asian (SAS) AF: 0.380 AC: 1831 AN: 4820

European-Finnish (FIN) AF: 0.307 AC: 3249 AN: 10576

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.335 AC: 22763 AN: 67964

Other (OTH) AF: 0.297 AC: 627 AN: 2114

Alfa AF: 0.316 Hom.: 12417

Bravo AF: 0.271

Asia WGS AF: 0.181 AC: 631 AN: 3478

EpiCase AF: 0.344

EpiControl AF: 0.342

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Dihydropteridine reductase deficiency (5)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	9.2
DANN	Benign	0.73
PhyloP100		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	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: rs2597775; hg19: chr4-17503382; COSMIC: COSV55552276;