rs3213422

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001361.5(DHODH):c.19A>C(p.Lys7Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 1,551,792 control chromosomes in the GnomAD database, including 214,917 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 22447 hom., cov: 34)

Exomes 𝑓: 0.52 ( 192470 hom. )

Consequence

DHODH
NM_001361.5 missense, splice_region

Scores

Splicing: ADA: 0.0003165

Clinical Significance

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

Conservation

PhyloP100: 1.21

Publications

78 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:

ENSG00000294600 (HGNC:):

ENSG00000294600 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=2.5988757E-6).

BP6

Variant 16-72008783-A-C is Benign according to our data. Variant chr16-72008783-A-C is described in ClinVar as Benign. ClinVar VariationId is 128895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHODH	NM_001361.5 link	c.19A>C	p.Lys7Gln	missense_variant, splice_region_variant	Exon 1 of 9	ENST00000219240.9	NP_001352.2	Q02127
DHODH	XM_047433674.1 link	c.-190A>C		5_prime_UTR_variant	Exon 1 of 9		XP_047289630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHODH	ENST00000219240.9 link	c.19A>C	p.Lys7Gln	missense_variant, splice_region_variant	Exon 1 of 9	1	NM_001361.5	ENSP00000219240.4		Q02127

Frequencies

GnomAD3 genomes

AF:

0.540

AC:

82091

AN:

152028

Hom.:

22430

Cov.:

show subpopulations

Gnomad AFR

AF:

0.547

Gnomad AMI

AF:

0.634

Gnomad AMR

AF:

0.616

Gnomad ASJ

AF:

0.525

Gnomad EAS

AF:

0.755

Gnomad SAS

AF:

0.473

Gnomad FIN

AF:

0.540

Gnomad MID

AF:

0.345

Gnomad NFE

AF:

0.509

Gnomad OTH

AF:

0.505

GnomAD2 exomes

AF:

0.554

AC:

86023

AN:

155404

AF XY:

0.542

show subpopulations

Gnomad AFR exome

AF:

0.545

Gnomad AMR exome

AF:

0.679

Gnomad ASJ exome

AF:

0.519

Gnomad EAS exome

AF:

0.778

Gnomad FIN exome

AF:

0.536

Gnomad NFE exome

AF:

0.507

Gnomad OTH exome

AF:

0.503

GnomAD4 exome

AF:

0.522

AC:

730105

AN:

1399646

Hom.:

192470

Cov.:

AF XY:

0.519

AC XY:

358109

AN XY:

690350

show subpopulations

African (AFR)

AF:

0.541

AC:

17121

AN:

31624

American (AMR)

AF:

0.670

AC:

23935

AN:

35720

Ashkenazi Jewish (ASJ)

AF:

0.517

AC:

13008

AN:

25180

East Asian (EAS)

AF:

0.712

AC:

25475

AN:

35760

South Asian (SAS)

AF:

0.465

AC:

36888

AN:

79256

European-Finnish (FIN)

AF:

0.529

AC:

26087

AN:

49352

Middle Eastern (MID)

AF:

0.382

AC:

2148

AN:

5622

European-Non Finnish (NFE)

AF:

0.514

AC:

555089

AN:

1079084

Other (OTH)

AF:

0.523

AC:

30354

AN:

58048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

21385

42770

64156

85541

106926

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16396

32792

49188

65584

81980

<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:

0.540

AC:

82156

AN:

152146

Hom.:

22447

Cov.:

AF XY:

0.545

AC XY:

40568

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.547

AC:

22693

AN:

41524

American (AMR)

AF:

0.616

AC:

9430

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.525

AC:

1821

AN:

3470

East Asian (EAS)

AF:

0.755

AC:

3903

AN:

5170

South Asian (SAS)

AF:

0.473

AC:

2278

AN:

4818

European-Finnish (FIN)

AF:

0.540

AC:

5713

AN:

10584

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.509

AC:

34568

AN:

67962

Other (OTH)

AF:

0.506

AC:

1069

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

2039

4078

6116

8155

10194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

710

1420

2130

2840

3550

<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:

0.520

Hom.:

94465

Bravo

AF:

0.550

TwinsUK

AF:

0.519

AC:

1924

ALSPAC

AF:

0.513

AC:

1976

ESP6500AA

AF:

0.585

AC:

2268

ESP6500EA

AF:

0.525

AC:

4234

ExAC

AF:

0.409

AC:

29023

Asia WGS

AF:

0.594

AC:

2064

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 16, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Miller syndrome

Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.10

.;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.67

T;T

MetaRNN

Benign

0.0000026

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.37

.;N

PhyloP100

1.2

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.57

.;N

REVEL

Uncertain

0.36

Sift

Benign

0.12

.;T

Sift4G

Benign

0.26

T;T

Polyphen

0.0020

.;B

Vest4

0.065

MPC

0.20

ClinPred

0.019

GERP RS

2.9

PromoterAI

0.014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.47

Mutation Taster

=81/19

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00032

dbscSNV1_RF

Benign

0.0

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