rs3213422

chr16-72008783-A-Cchr16-72008783-A-Gchr16-72008783-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/22 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:7
• Conservation: PhyloP100: 1.21

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=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 id is 128895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-72008783-A-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
DHODH	NM_001361.5	c.19A>C	p.Lys7Gln	missense_variant, splice_region_variant	1/9	ENST00000219240.9
DHODH	XM_047433674.1	c.-190A>C		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHODH	ENST00000219240.9	c.19A>C	p.Lys7Gln	missense_variant, splice_region_variant	1/9	1	NM_001361.5	P3

Frequencies

GnomAD3 genomes AF: 0.540 AC: 82091 AN: 152028 Hom.: 22430 Cov.: 34

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

GnomAD3 exomes AF: 0.554 AC: 86023 AN: 155404 Hom.: 24624 AF XY: 0.542 AC XY: 44582 AN XY: 82214

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 SAS exome AF: 0.472

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.: 68 AF XY: 0.519 AC XY: 358109 AN XY: 690350

Gnomad4 AFR exome AF: 0.541

Gnomad4 AMR exome AF: 0.670

Gnomad4 ASJ exome AF: 0.517

Gnomad4 EAS exome AF: 0.712

Gnomad4 SAS exome AF: 0.465

Gnomad4 FIN exome AF: 0.529

Gnomad4 NFE exome AF: 0.514

Gnomad4 OTH exome AF: 0.523

GnomAD4 genome AF: 0.540 AC: 82156 AN: 152146 Hom.: 22447 Cov.: 34 AF XY: 0.545 AC XY: 40568 AN XY: 74382

Gnomad4 AFR AF: 0.547

Gnomad4 AMR AF: 0.616

Gnomad4 ASJ AF: 0.525

Gnomad4 EAS AF: 0.755

Gnomad4 SAS AF: 0.473

Gnomad4 FIN AF: 0.540

Gnomad4 NFE AF: 0.509

Gnomad4 OTH AF: 0.506

Alfa AF: 0.517 Hom.: 50995

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Miller syndrome Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	19
Dann	Benign	0.89
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0000026	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	0.97	P;P
PrimateAI	Benign	0.42	T
Sift4G	Benign	0.26	T;T
Polyphen		0.0020	.;B
Vest4		0.065
MPC		0.20
ClinPred		0.019	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.47

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

LitVar

Other links and lift over

dbSNP: rs3213422; hg19: chr16-72042682; COSMIC: COSV54662830; COSMIC: COSV54662830;