16-72008783-A-C

Position:

chr16-72008783-A-C

Variant summary

Our verdict is Benign. Variant got -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. 15/22 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:8

Conservation

PhyloP100: 1.21

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=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	Protein	UniProt
DHODH	NM_001361.5 linkuse as main transcript	c.19A>C	p.Lys7Gln	missense_variant, splice_region_variant	1/9	ENST00000219240.9	NP_001352.2
DHODH	XM_047433674.1 linkuse as main transcript	c.-190A>C		5_prime_UTR_variant	1/9		XP_047289630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHODH	ENST00000219240.9 linkuse as main transcript	c.19A>C	p.Lys7Gln	missense_variant, splice_region_variant	1/9	1	NM_001361.5	ENSP00000219240	P3

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

GnomAD3 exomes

AF:

0.554

AC:

86023

AN:

155404

Hom.:

24624

AF XY:

0.542

AC XY:

44582

AN XY:

82214

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 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.:

AF XY:

0.519

AC XY:

358109

AN XY:

690350

show subpopulations

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.:

AF XY:

0.545

AC XY:

40568

AN XY:

74382

show subpopulations

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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 -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	- -

Miller syndrome

Benign:2

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

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

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

MutationTaster

Benign

0.97

P;P

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

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

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