16-72021211-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5

The NM_001361.5(DHODH):c.605G>A(p.Gly202Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,611,664 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G202A) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

DHODH
NM_001361.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.80

Publications

18 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P

DHODH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-72021211-G-C is described in CliVar as Pathogenic. Clinvar id is 16804.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.926

PP5

Variant 16-72021211-G-A is Pathogenic according to our data. Variant chr16-72021211-G-A is described in CliVar as Pathogenic. Clinvar id is 16805.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-72021211-G-A is described in CliVar as Pathogenic. Clinvar id is 16805.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-72021211-G-A is described in CliVar as Pathogenic. Clinvar id is 16805.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-72021211-G-A is described in CliVar as Pathogenic. Clinvar id is 16805.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-72021211-G-A is described in CliVar as Pathogenic. Clinvar id is 16805.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-72021211-G-A is described in CliVar as Pathogenic. Clinvar id is 16805.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-72021211-G-A is described in CliVar as Pathogenic. Clinvar id is 16805.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-72021211-G-A is described in CliVar as Pathogenic. Clinvar id is 16805.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-72021211-G-A is described in CliVar as Pathogenic. Clinvar id is 16805.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-72021211-G-A is described in CliVar as Pathogenic. Clinvar id is 16805.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-72021211-G-A is described in CliVar as Pathogenic. Clinvar id is 16805.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHODH	NM_001361.5 link	c.605G>A	p.Gly202Asp	missense_variant	Exon 5 of 9	ENST00000219240.9	NP_001352.2	Q02127
DHODH	XM_047433674.1 link	c.521G>A	p.Gly174Asp	missense_variant	Exon 5 of 9		XP_047289630.1
DHODH	XM_005255829.5 link	c.176G>A	p.Gly59Asp	missense_variant	Exon 3 of 7		XP_005255886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHODH	ENST00000219240.9 link	c.605G>A	p.Gly202Asp	missense_variant	Exon 5 of 9	1	NM_001361.5	ENSP00000219240.4		Q02127

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000372

AC:

AN:

242182

AF XY:

0.0000456

show subpopulations

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 FIN exome

AF:

0.0000486

Gnomad NFE exome

AF:

0.0000273

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000548

AC:

AN:

1459374

Hom.:

Cov.:

AF XY:

0.0000689

AC XY:

AN XY:

725742

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44372

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26046

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39594

South Asian (SAS)

AF:

0.0000934

AC:

AN:

85642

European-Finnish (FIN)

AF:

0.0000377

AC:

AN:

53060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000585

AC:

AN:

1111154

Other (OTH)

AF:

0.0000663

AC:

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41564

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

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:

0.000290

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000413

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Miller syndrome

Pathogenic:1

Jan 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

.;D

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

3.8

.;H

PhyloP100

9.8

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.3

.;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0040

.;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.97

.;D

Vest4

0.93

MutPred

0.73

Gain of helix (P = 0.132);Gain of helix (P = 0.132);

MVP

0.94

MPC

0.85

ClinPred

0.85

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.82

Mutation Taster

=8/92

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over