rs61733129

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001361.5(DHODH):c.1022C>T(p.Ala341Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,614,036 control chromosomes in the GnomAD database, including 798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A341T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.023 ( 60 hom., cov: 33)

Exomes 𝑓: 0.029 ( 738 hom. )

Consequence

DHODH
NM_001361.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.52

Publications

20 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:

ENSG00000289937 (HGNC:):

ENSG00000289937 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0088287).

BP6

Variant 16-72023522-C-T is Benign according to our data. Variant chr16-72023522-C-T is described in ClinVar as Benign. ClinVar VariationId is 128894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0227 (3462/152228) while in subpopulation EAS AF = 0.0499 (258/5170). AF 95% confidence interval is 0.0449. There are 60 homozygotes in GnomAd4. There are 1702 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 60 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHODH	NM_001361.5	MANE Select	c.1022C>T	p.Ala341Val	missense	Exon 8 of 9	NP_001352.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DHODH	ENST00000219240.9	TSL:1 MANE Select	c.1022C>T	p.Ala341Val	missense	Exon 8 of 9	ENSP00000219240.4
DHODH	ENST00000572887.5	TSL:5	c.1016C>T	p.Ala339Val	missense	Exon 8 of 9	ENSP00000461848.1
DHODH	ENST00000571392.1	TSL:5	n.1686C>T		non_coding_transcript_exon	Exon 3 of 4

Frequencies

GnomAD3 genomes

AF:

0.0228

AC:

3462

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00599

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0191

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.0498

Gnomad SAS

AF:

0.0251

Gnomad FIN

AF:

0.0251

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0313

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0274

AC:

6841

AN:

249458

AF XY:

0.0280

show subpopulations

Gnomad AFR exome

AF:

0.00549

Gnomad AMR exome

AF:

0.0224

Gnomad ASJ exome

AF:

0.0244

Gnomad EAS exome

AF:

0.0517

Gnomad FIN exome

AF:

0.0276

Gnomad NFE exome

AF:

0.0295

Gnomad OTH exome

AF:

0.0200

GnomAD4 exome

AF:

0.0290

AC:

42458

AN:

1461808

Hom.:

738

Cov.:

AF XY:

0.0291

AC XY:

21162

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00609

AC:

204

AN:

33480

American (AMR)

AF:

0.0209

AC:

935

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0224

AC:

585

AN:

26136

East Asian (EAS)

AF:

0.0503

AC:

1996

AN:

39700

South Asian (SAS)

AF:

0.0248

AC:

2137

AN:

86252

European-Finnish (FIN)

AF:

0.0264

AC:

1412

AN:

53412

Middle Eastern (MID)

AF:

0.0291

AC:

166

AN:

5704

European-Non Finnish (NFE)

AF:

0.0300

AC:

33381

AN:

1112008

Other (OTH)

AF:

0.0272

AC:

1642

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

2700

5399

8099

10798

13498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1248

2496

3744

4992

6240

<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:

0.0227

AC:

3462

AN:

152228

Hom.:

Cov.:

AF XY:

0.0229

AC XY:

1702

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00597

AC:

248

AN:

41550

American (AMR)

AF:

0.0191

AC:

292

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3470

East Asian (EAS)

AF:

0.0499

AC:

258

AN:

5170

South Asian (SAS)

AF:

0.0253

AC:

122

AN:

4814

European-Finnish (FIN)

AF:

0.0251

AC:

266

AN:

10602

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0313

AC:

2129

AN:

68012

Other (OTH)

AF:

0.0270

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

183

367

550

734

917

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0280

Hom.:

153

Bravo

AF:

0.0208

TwinsUK

AF:

0.0294

AC:

109

ALSPAC

AF:

0.0275

AC:

106

ESP6500AA

AF:

0.00633

AC:

ESP6500EA

AF:

0.0269

AC:

225

ExAC

AF:

0.0269

AC:

3259

Asia WGS

AF:

0.0470

AC:

165

AN:

3478

EpiCase

AF:

0.0291

EpiControl

AF:

0.0318

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (2)

Miller syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.0088

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

2.9

PhyloP100

7.5

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.3

REVEL

Pathogenic

0.85

Sift

Benign

0.043

Sift4G

Uncertain

0.042

Polyphen

1.0

Vest4

0.35

MPC

0.69

ClinPred

0.014

GERP RS

4.5

Varity_R

0.70

gMVP

0.86

Mutation Taster

=59/41

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over