Genetic Variant NM_001361.5:c.730C>T (chr16-72022386-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001361.5(DHODH):c.730C>T(p.Arg244Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,554,930 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R244Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

DHODH
NM_001361.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 0.718

Publications

8 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 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

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.730C>T	p.Arg244Trp	missense	Exon 6 of 9	NP_001352.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DHODH	ENST00000219240.9	TSL:1 MANE Select	c.730C>T	p.Arg244Trp	missense	Exon 6 of 9	ENSP00000219240.4
DHODH	ENST00000894311.1		c.916C>T	p.Arg306Trp	missense	Exon 8 of 11	ENSP00000564370.1
DHODH	ENST00000894313.1		c.727C>T	p.Arg243Trp	missense	Exon 6 of 9	ENSP00000564372.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152142

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:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000107

AC:

AN:

1402670

Hom.:

Cov.:

AF XY:

0.00000722

AC XY:

AN XY:

692192

show subpopulations

African (AFR)

AF:

0.0000629

AC:

AN:

31816

American (AMR)

AF:

0.00

AC:

AN:

36194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25210

East Asian (EAS)

AF:

0.00

AC:

AN:

36122

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79420

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49116

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.0000102

AC:

AN:

1081002

Other (OTH)

AF:

0.0000172

AC:

AN:

58132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.452

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:

0.0000197

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41552

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.0000385

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Miller syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.9

PhyloP100

0.72

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.56

Sift

Uncertain

0.012

Sift4G

Uncertain

0.016

Polyphen

0.98

Vest4

0.70

MutPred

0.86

Loss of disorder (P = 0.0016)

MVP

0.97

MPC

0.56

ClinPred

0.75

GERP RS

-1.4

Varity_R

0.56

gMVP

0.37

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over