NM_000320.3:c.199-66C>T

Variant names:

• chr4-17504541-G-A
• rs2315248
• NM_000320.3:c.199-66C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000320.3(QDPR):​c.199-66C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 1,271,074 control chromosomes in the GnomAD database, including 19,142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2080 hom., cov: 33)
  • Exomes 𝑓: 0.17 (17062 hom.)
• Consequence: QDPR NM_000320.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.897
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-17504541-G-A is Benign according to our data. Variant chr4-17504541-G-A is described in ClinVar as Benign. ClinVar VariationId is 1288544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
QDPR	NM_000320.3	c.199-66C>T		intron_variant	Intron 2 of 6	ENST00000281243.10	NP_000311.2
QDPR	NM_001306140.2	c.106-66C>T		intron_variant	Intron 1 of 5		NP_001293069.1
QDPR	NR_156494.2	n.235-66C>T		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
QDPR	ENST00000281243.10	c.199-66C>T		intron_variant	Intron 2 of 6	1	NM_000320.3	ENSP00000281243.5

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24225 AN: 152020 Hom.: 2083 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.189

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.179

Gnomad OTH AF: 0.181

GnomAD4 exome AF: 0.172 AC: 192724 AN: 1118936 Hom.: 17062 AF XY: 0.170 AC XY: 97468 AN XY: 572356

African (AFR) AF: 0.122 AC: 3259 AN: 26684

American (AMR) AF: 0.220 AC: 9609 AN: 43580

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 4999 AN: 23958

East Asian (EAS) AF: 0.0929 AC: 3529 AN: 37998

South Asian (SAS) AF: 0.129 AC: 10109 AN: 78578

European-Finnish (FIN) AF: 0.125 AC: 6629 AN: 53142

Middle Eastern (MID) AF: 0.180 AC: 920 AN: 5112

European-Non Finnish (NFE) AF: 0.181 AC: 145042 AN: 800810

Other (OTH) AF: 0.176 AC: 8628 AN: 49074

GnomAD4 genome AF: 0.159 AC: 24241 AN: 152138 Hom.: 2080 Cov.: 33 AF XY: 0.157 AC XY: 11650 AN XY: 74366

African (AFR) AF: 0.120 AC: 4986 AN: 41506

American (AMR) AF: 0.221 AC: 3379 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 737 AN: 3470

East Asian (EAS) AF: 0.106 AC: 552 AN: 5184

South Asian (SAS) AF: 0.125 AC: 601 AN: 4812

European-Finnish (FIN) AF: 0.116 AC: 1232 AN: 10582

Middle Eastern (MID) AF: 0.199 AC: 58 AN: 292

European-Non Finnish (NFE) AF: 0.179 AC: 12142 AN: 67990

Other (OTH) AF: 0.181 AC: 382 AN: 2110

Alfa AF: 0.162 Hom.: 346

Bravo AF: 0.167

Asia WGS AF: 0.126 AC: 438 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.6
DANN	Benign	0.73
PhyloP100		0.90
Mutation Taster		=100/0	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: rs2315248; hg19: chr4-17506164; COSMIC: COSV55549900;