rs267606769

chr16-72021201-C-Achr16-72021201-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001361.5(DHODH):c.595C>A(p.Arg199Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,446 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R199C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DHODH NM_001361.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.81

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-72021201-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 16808.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHODH	NM_001361.5	c.595C>A	p.Arg199Ser	missense_variant	5/9	ENST00000219240.9
DHODH	XM_047433674.1	c.511C>A	p.Arg171Ser	missense_variant	5/9
DHODH	XM_005255829.5	c.166C>A	p.Arg56Ser	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHODH	ENST00000219240.9	c.595C>A	p.Arg199Ser	missense_variant	5/9	1	NM_001361.5	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000416 AC: 1 AN: 240532 Hom.: 0 AF XY: 0.00000765 AC XY: 1 AN XY: 130732

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: 0.0000338

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458446 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725198

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Uncertain	0.0
Cadd	Benign	23
Dann	Benign	0.96
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.038
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.14	D
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.48	T
Sift4G	Benign	0.16	T;T
Polyphen		0.43	.;B
Vest4		0.74
MutPred		0.63		Gain of glycosylation at R199 (P = 0.0377);Gain of glycosylation at R199 (P = 0.0377);
MVP		0.97
MPC		0.44
ClinPred		0.55	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs267606769; hg19: chr16-72055100;