16-72008783-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001361.5(DHODH):c.19A>G(p.Lys7Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K7Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DHODH NM_001361.5 missense, splice_region
• Scores: Splicing: ADA: 0.0004097
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21

Genes affected

DHODH (HGNC:2867): (dihydroorotate dehydrogenase (quinone)) The protein encoded by this gene catalyzes the fourth enzymatic step, the ubiquinone-mediated oxidation of dihydroorotate to orotate, in de novo pyrimidine biosynthesis. This protein is a mitochondrial protein located on the outer surface of the inner mitochondrial membrane. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20265463).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHODH	NM_001361.5	c.19A>G	p.Lys7Glu	missense_variant, splice_region_variant	1/9	ENST00000219240.9
DHODH	XM_047433674.1	c.-190A>G		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHODH	ENST00000219240.9	c.19A>G	p.Lys7Glu	missense_variant, splice_region_variant	1/9	1	NM_001361.5	P3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.14e-7 AC: 1 AN: 1399688 Hom.: 0 Cov.: 68 AF XY: 0.00 AC XY: 0 AN XY: 690370

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Uncertain	-0.25	T
MutationTaster	Benign	0.96	P;P
PrimateAI	Benign	0.45	T
Sift4G	Benign	0.11	T;T
Polyphen		0.059	.;B
Vest4		0.14
MutPred		0.30		Loss of MoRF binding (P = 0.0053);Loss of MoRF binding (P = 0.0053);
MVP		0.86
MPC		0.28
ClinPred		0.20	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00041
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 15

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3213422; hg19: chr16-72042682;