rs201230446

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PS3PP3PP5_Very_StrongBP4

The NM_001361.5(DHODH):c.403C>T(p.Arg135Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000463 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000398764: Functional studies utilizing in vitro biochemical analysis in HeLa cell lines that stably expressed the variant protein demonstrated reduced activity of the DHODH enzyme compared to wild type (Fang et al. 2012" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00046 ( 0 hom. )

Consequence

DHODH
NM_001361.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 3.32

Publications

29 publications found

Variant links:

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]

DHODH Gene-Disease associations (from GenCC):

postaxial acrofacial dysostosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

DHODH links:

ENSG00000294600 (HGNC:):

ENSG00000294600 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000398764: Functional studies utilizing in vitro biochemical analysis in HeLa cell lines that stably expressed the variant protein demonstrated reduced activity of the DHODH enzyme compared to wild type (Fang et al. 2012; Rainger et al. 2012).; SCV000967609: "In vitro functional studies provide some evidence that the p.Arg135Cys variant may impact protein function (Rainger 2012, Fang 2012)"; SCV004029295: "At least two publications report experimental evidence evaluating an impact on protein function, finding substantial reductions in enzymatic activity (Fang_2012, Rainger_2012)."; SCV000329336: "Published in vitro assays demonstrate R135C results in a significant decrease in DHO-dependent reductase activity (PMID: 22967083)"; SCV002129025: Experimental studies have shown that this missense change affects DHODH function (PMID: 22692683, 22967083).

PP3

Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when Dann, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

PP5

Variant 16-72014641-C-T is Pathogenic according to our data. Variant chr16-72014641-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.2148906). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001361.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHODH	NM_001361.5	MANE Select	c.403C>T	p.Arg135Cys	missense	Exon 3 of 9	NP_001352.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DHODH	ENST00000219240.9	TSL:1 MANE Select	c.403C>T	p.Arg135Cys	missense	Exon 3 of 9	ENSP00000219240.4	Q02127
DHODH	ENST00000894311.1		c.403C>T	p.Arg135Cys	missense	Exon 3 of 11	ENSP00000564370.1
DHODH	ENST00000894313.1		c.400C>T	p.Arg134Cys	missense	Exon 3 of 9	ENSP00000564372.1

Frequencies

GnomAD3 genomes

AF:

0.000519

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000353

AC:

AN:

249496

AF XY:

0.000384

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000707

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000458

AC:

669

AN:

1461854

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

323

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.000179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000573

AC:

637

AN:

1112008

Other (OTH)

AF:

0.000348

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

121

162

202

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000519

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41562

American (AMR)

AF:

0.000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68018

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000499

Hom.:

Bravo

AF:

0.000669

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000607

AC:

ExAC

AF:

0.000381

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Miller syndrome (6)

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.91

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.21

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.3

PhyloP100

3.3

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-7.6

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MVP

0.97

MPC

0.87

ClinPred

0.95

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.84

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over