NM_000320.3:c.322T>G

Variant names:

• chr4-17501833-A-C
• rs104893864
• NM_000320.3:c.322T>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 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
• Publications: 5 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000320.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: 0.28456 (below the threshold of 3.09). Trascript score misZ: 0.32173 (below the threshold of 3.09). GenCC associations: The gene is linked to dihydropteridine reductase deficiency.
• 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 VariationId is 491.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
QDPR	NM_000320.3	c.322T>G	p.Trp108Gly	missense_variant	Exon 4 of 7	ENST00000281243.10	NP_000311.2
QDPR	NM_001306140.2	c.229T>G	p.Trp77Gly	missense_variant	Exon 3 of 6		NP_001293069.1
QDPR	NR_156494.2	n.358T>G		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.322T>G	p.Trp108Gly	missense_variant	Exon 4 of 7	1	NM_000320.3	ENSP00000281243.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Dihydropteridine reductase deficiency Pathogenic:1

Jun 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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;.;.
PhyloP100		8.5
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
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs104893864; hg19: chr4-17503456;