4-17486441-T-C

Variant names:

• chr4-17486441-T-C
• rs1031326
• NM_000320.3:c.*690A>G

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.*690A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 151,888 control chromosomes in the GnomAD database, including 28,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (28899 hom., cov: 32)
  • Exomes 𝑓: 0.47 (30 hom.)
• Consequence: QDPR NM_000320.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.25
• Publications: 11 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=-0.93).
• BP6: Variant 4-17486441-T-C is Benign according to our data. Variant chr4-17486441-T-C is described in ClinVar as Benign. ClinVar VariationId is 348137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QDPR	NM_000320.3	MANE Select	c.*690A>G		3_prime_UTR	Exon 7 of 7	NP_000311.2
	QDPR	NR_156494.2		n.1352A>G		non_coding_transcript_exon	Exon 6 of 6
	QDPR	NM_001306140.2		c.*690A>G		3_prime_UTR	Exon 6 of 6	NP_001293069.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	QDPR	ENST00000281243.10	TSL:1 MANE Select	c.*690A>G		3_prime_UTR	Exon 7 of 7	ENSP00000281243.5
	QDPR	ENST00000507439.5	TSL:2	n.*857A>G		non_coding_transcript_exon	Exon 6 of 6	ENSP00000423227.1
	QDPR	ENST00000706645.1		n.2472A>G		non_coding_transcript_exon	Exon 6 of 6

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93243 AN: 151558 Hom.: 28864 Cov.: 32

Gnomad AFR AF: 0.557

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.537

Gnomad EAS AF: 0.705

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.718

Gnomad MID AF: 0.673

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.618

GnomAD4 exome AF: 0.467 AC: 99 AN: 212 Hom.: 30 Cov.: 0 AF XY: 0.469 AC XY: 61 AN XY: 130

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.368 AC: 14 AN: 38

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.333 AC: 2 AN: 6

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 81 AN: 162

Other (OTH) AF: 0.333 AC: 2 AN: 6

GnomAD4 genome AF: 0.615 AC: 93325 AN: 151676 Hom.: 28899 Cov.: 32 AF XY: 0.622 AC XY: 46111 AN XY: 74102

African (AFR) AF: 0.557 AC: 23037 AN: 41324

American (AMR) AF: 0.575 AC: 8770 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 1860 AN: 3464

East Asian (EAS) AF: 0.705 AC: 3610 AN: 5118

South Asian (SAS) AF: 0.637 AC: 3061 AN: 4806

European-Finnish (FIN) AF: 0.718 AC: 7571 AN: 10540

Middle Eastern (MID) AF: 0.686 AC: 199 AN: 290

European-Non Finnish (NFE) AF: 0.638 AC: 43320 AN: 67852

Other (OTH) AF: 0.618 AC: 1305 AN: 2110

Alfa AF: 0.628 Hom.: 126602

Bravo AF: 0.599

Asia WGS AF: 0.655 AC: 2281 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dihydropteridine reductase deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.12
DANN	Benign	0.44
PhyloP100		-2.2
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: rs1031326; hg19: chr4-17488064;