chr16-72012206-C-T

Variant names:

• chr16-72012206-C-T
• rs931958752
• NM_001361.5:c.178C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001361.5(DHODH):​c.178C>T​(p.Arg60Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000752 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: DHODH NM_001361.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.89

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHODH	NM_001361.5	c.178C>T	p.Arg60Cys	missense_variant	Exon 2 of 9	ENST00000219240.9	NP_001352.2
DHODH	XM_047433674.1	c.94C>T	p.Arg32Cys	missense_variant	Exon 2 of 9		XP_047289630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHODH	ENST00000219240.9	c.178C>T	p.Arg60Cys	missense_variant	Exon 2 of 9	1	NM_001361.5	ENSP00000219240.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249576 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135400

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727244

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.55	.;D;T
Eigen	Benign	-0.011
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.5	.;M;.
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.5	.;D;.
REVEL	Uncertain	0.45
Sift	Benign	0.091	.;T;.
Sift4G	Benign	0.11	T;T;T
Polyphen		0.081	.;B;.
Vest4		0.61
MutPred		0.61		Loss of methylation at R60 (P = 0.007);Loss of methylation at R60 (P = 0.007);.;
MVP		0.96
MPC		0.41
ClinPred		0.90	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.37
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs931958752; hg19: chr16-72046105; COSMIC: COSV54662060; COSMIC: COSV54662060;