rs104893864

Positions:

• chr4-17501833-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000320.3(QDPR):​c.322T>G​(p.Trp108Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: QDPR NM_000320.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.48

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a chain Dihydropteridine reductase (size 242) in uniprot entity DHPR_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_000320.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 4-17501833-A-C is Pathogenic according to our data. Variant chr4-17501833-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 491.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
QDPR	NM_000320.3	c.322T>G	p.Trp108Gly	missense_variant	4/7	ENST00000281243.10	NP_000311.2
QDPR	NM_001306140.2	c.229T>G	p.Trp77Gly	missense_variant	3/6		NP_001293069.1
QDPR	NR_156494.2	n.358T>G		non_coding_transcript_exon_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
QDPR	ENST00000281243.10	c.322T>G	p.Trp108Gly	missense_variant	4/7	1	NM_000320.3	ENSP00000281243.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Dihydropteridine reductase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T;D;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	3.3	.;M;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-12	D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.015	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.087	.;B;.;.
Vest4		0.95
MutPred		0.81		Loss of catalytic residue at L106 (P = 0.0047);Loss of catalytic residue at L106 (P = 0.0047);.;Loss of catalytic residue at L106 (P = 0.0047);
MVP		0.96
MPC		0.51
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.90

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: rs104893864; hg19: chr4-17503456;