rs1407920390

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000320.3(QDPR):​c.344C>T​(p.Ser115Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S115S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

QDPR
NM_000320.3 missense

Scores

12
5
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 7.26
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 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, 0.961
PP5
Variant 4-17501811-G-A is Pathogenic according to our data. Variant chr4-17501811-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 459896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
QDPRNM_000320.3 linkuse as main transcriptc.344C>T p.Ser115Leu missense_variant 4/7 ENST00000281243.10 NP_000311.2 P09417-1A0A140VKA9
QDPRNM_001306140.2 linkuse as main transcriptc.251C>T p.Ser84Leu missense_variant 3/6 NP_001293069.1 P09417-2
QDPRNR_156494.2 linkuse as main transcriptn.380C>T non_coding_transcript_exon_variant 4/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
QDPRENST00000281243.10 linkuse as main transcriptc.344C>T p.Ser115Leu missense_variant 4/71 NM_000320.3 ENSP00000281243.5 P09417-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251154
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135732
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000616
AC:
9
AN:
1461866
Hom.:
0
Cov.:
35
AF XY:
0.00000688
AC XY:
5
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000847
Hom.:
0
Bravo
AF:
0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Dihydropteridine reductase deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingPathology and Clinical Laboratory Medicine, King Fahad Medical City-- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 06, 2023This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 115 of the QDPR protein (p.Ser115Leu). This variant is present in population databases (no rsID available, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 459896). This missense change has been observed in individual(s) with BH4 deficiency (PMID: 26006720). -
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 21, 2023Observed with a second QDPR variant in a patient with BH4-deficient hyperphenylalaninemia in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Gundorova et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33152132, 27527004, 33903016, 26006720, 27246466, 33822819) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.51
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.24
T;D;.;.
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
.;D;D;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.96
D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.1
.;M;.;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-6.0
D;D;D;D
REVEL
Pathogenic
0.81
Sift
Uncertain
0.0010
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;T;D
Polyphen
1.0
.;D;.;.
Vest4
0.93
MutPred
0.74
Loss of disorder (P = 0.0403);Loss of disorder (P = 0.0403);.;Loss of disorder (P = 0.0403);
MVP
0.98
MPC
0.70
ClinPred
0.99
D
GERP RS
5.7
Varity_R
0.91
gMVP
0.95

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1407920390; hg19: chr4-17503434; API