rs61733129

chr16-72023522-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 7.52

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 60 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3462 AN: 152110 Hom.: 60 Cov.: 33

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

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.: 34 AF XY: 0.0291 AC XY: 21162 AN XY: 727208

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.: 60 Cov.: 33 AF XY: 0.0229 AC XY: 1702 AN XY: 74424

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: 26

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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	T
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Uncertain	0.20	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
Sift4G	Uncertain	0.042	D;D
Polyphen		1.0	.;D
Vest4		0.35
MPC		0.69
ClinPred		0.014	T
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

Other links and lift over

dbSNP: rs61733129; hg19: chr16-72057421; COSMIC: COSV54663141; COSMIC: COSV54663141;