4-17486911-A-G

Position:

• chr4-17486911-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000320.3(QDPR):​c.*220T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 581,236 control chromosomes in the GnomAD database, including 133,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32423 hom., cov: 33)
  • Exomes 𝑓: 0.68 (101387 hom.)
• Consequence: QDPR NM_000320.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.878

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 4-17486911-A-G is Benign according to our data. Variant chr4-17486911-A-G is described in ClinVar as [Benign]. Clinvar id is 348151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
QDPR	NM_000320.3	c.*220T>C		3_prime_UTR_variant	7/7	ENST00000281243.10
QDPR	NM_001306140.2	c.*220T>C		3_prime_UTR_variant	6/6
QDPR	NR_156494.2	n.882T>C		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
QDPR	ENST00000281243.10	c.*220T>C		3_prime_UTR_variant	7/7	1	NM_000320.3	P1

Frequencies

GnomAD3 genomes AF: 0.651 AC: 98545 AN: 151480 Hom.: 32395 Cov.: 33

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.661

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.683

Gnomad FIN AF: 0.793

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.648

GnomAD4 exome AF: 0.684 AC: 293734 AN: 429638 Hom.: 101387 Cov.: 3 AF XY: 0.684 AC XY: 156880 AN XY: 229228

Gnomad4 AFR exome AF: 0.580

Gnomad4 AMR exome AF: 0.553

Gnomad4 ASJ exome AF: 0.564

Gnomad4 EAS exome AF: 0.798

Gnomad4 SAS exome AF: 0.687

Gnomad4 FIN exome AF: 0.780

Gnomad4 NFE exome AF: 0.683

Gnomad4 OTH exome AF: 0.672

GnomAD4 genome AF: 0.651 AC: 98620 AN: 151598 Hom.: 32423 Cov.: 33 AF XY: 0.658 AC XY: 48737 AN XY: 74046

Gnomad4 AFR AF: 0.565

Gnomad4 AMR AF: 0.600

Gnomad4 ASJ AF: 0.558

Gnomad4 EAS AF: 0.765

Gnomad4 SAS AF: 0.683

Gnomad4 FIN AF: 0.793

Gnomad4 NFE AF: 0.685

Gnomad4 OTH AF: 0.648

Alfa AF: 0.666 Hom.: 19431

Bravo AF: 0.629

Asia WGS AF: 0.709 AC: 2468 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2018	- -

Dihydropteridine reductase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.6
DANN	Benign	0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1049581; hg19: chr4-17488534;