chr4-17504404-C-T

Variant names:

• chr4-17504404-C-T
• rs104893867
• NM_000320.3:c.270G>A

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000320.3(QDPR):​c.270G>A​(p.Trp90*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: QDPR NM_000320.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.10
• Publications: 2 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-17504404-C-T is Pathogenic according to our data. Variant chr4-17504404-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 495.Status of the report is no_assertion_criteria_provided, 0 stars.

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.270G>A	p.Trp90*	stop_gained	Exon 3 of 7	NP_000311.2	A0A140VKA9
	QDPR	NM_001306140.2		c.177G>A	p.Trp59*	stop_gained	Exon 2 of 6	NP_001293069.1	P09417-2
	QDPR	NR_156494.2		n.306G>A		non_coding_transcript_exon	Exon 3 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QDPR	ENST00000281243.10	TSL:1 MANE Select	c.270G>A	p.Trp90*	stop_gained	Exon 3 of 7	ENSP00000281243.5	P09417-1
	QDPR	ENST00000910937.1		c.270G>A	p.Trp90*	stop_gained	Exon 3 of 7	ENSP00000580996.1
	QDPR	ENST00000910936.1		c.270G>A	p.Trp90*	stop_gained	Exon 3 of 8	ENSP00000580995.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Dihydropteridine reductase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		7.1
Vest4		0.98
ClinPred		1.0	D
GERP RS		5.5
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs104893867; hg19: chr4-17506027;