rs61733129

Positions:

chr16-72023522-C-T

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 128894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-72023522-C-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 60 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DHODH	NM_001361.5 linkuse as main transcript	c.1022C>T	p.Ala341Val	missense_variant	8/9	ENST00000219240.9
DHODH	XM_047433674.1 linkuse as main transcript	c.938C>T	p.Ala313Val	missense_variant	8/9
DHODH	XM_005255829.5 linkuse as main transcript	c.593C>T	p.Ala198Val	missense_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DHODH	ENST00000219240.9 linkuse as main transcript	c.1022C>T	p.Ala341Val	missense_variant	8/9	1	NM_001361.5	P3
DHODH	ENST00000572887.5 linkuse as main transcript	c.1016C>T	p.Ala339Val	missense_variant	8/9	5		A1
DHODH	ENST00000574309.5 linkuse as main transcript	c.514-623C>T		intron_variant		5
DHODH	ENST00000571392.1 linkuse as main transcript	n.1686C>T		non_coding_transcript_exon_variant	3/4	5

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

GnomAD3 exomes

AF:

0.0274

AC:

6841

AN:

249458

Hom.:

132

AF XY:

0.0280

AC XY:

3795

AN XY:

135358

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 SAS exome

AF:

0.0245

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

Gnomad4 AFR exome

AF:

0.00609

Gnomad4 AMR exome

AF:

0.0209

Gnomad4 ASJ exome

AF:

0.0224

Gnomad4 EAS exome

AF:

0.0503

Gnomad4 SAS exome

AF:

0.0248

Gnomad4 FIN exome

AF:

0.0264

Gnomad4 NFE exome

AF:

0.0300

Gnomad4 OTH exome

AF:

0.0272

GnomAD4 genome

AF:

0.0227

AC:

3462

AN:

152228

Hom.:

Cov.:

AF XY:

0.0229

AC XY:

1702

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00597

Gnomad4 AMR

AF:

0.0191

Gnomad4 ASJ

AF:

0.0225

Gnomad4 EAS

AF:

0.0499

Gnomad4 SAS

AF:

0.0253

Gnomad4 FIN

AF:

0.0251

Gnomad4 NFE

AF:

0.0313

Gnomad4 OTH

AF:

0.0270

Alfa

AF:

0.0293

Hom.:

124

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

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Miller syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

0.18

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.71

.;D

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

MetaRNN

Benign

0.0088

T;T

MetaSVM

Uncertain

0.20

MutationAssessor

Pathogenic

2.9

.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.3

.;D

REVEL

Pathogenic

0.85

Sift

Benign

0.043

.;D

Sift4G

Uncertain

0.042

D;D

Polyphen

1.0

.;D

Vest4

0.35

MPC

0.69

ClinPred

0.014

GERP RS

4.5

Varity_R

0.70

gMVP

0.86

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over