chr16-72017043-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001361.5(DHODH):c.454G>A(p.Gly152Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

DHODH
NM_001361.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 9.18

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHODH	NM_001361.5 link	c.454G>A	p.Gly152Arg	missense_variant	Exon 4 of 9	ENST00000219240.9	NP_001352.2	Q02127
DHODH	XM_047433674.1 link	c.370G>A	p.Gly124Arg	missense_variant	Exon 4 of 9		XP_047289630.1
DHODH	XM_005255829.5 link	c.25G>A	p.Gly9Arg	missense_variant	Exon 2 of 7		XP_005255886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHODH	ENST00000219240.9 link	c.454G>A	p.Gly152Arg	missense_variant	Exon 4 of 9	1	NM_001361.5	ENSP00000219240.4		Q02127

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000761

AC:

AN:

249544

Hom.:

AF XY:

0.0000812

AC XY:

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000151

AC:

221

AN:

1461798

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

103

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.000187

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152018

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000199

Hom.:

Bravo

AF:

0.0000567

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000993

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Miller syndrome

Pathogenic:1Uncertain:1

Jan 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 19, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DHODH c.454G>A (p.Gly152Arg) variant is a missense variant that has been identified in a compound heterozygous state in two siblings with Miller syndrome, another name for postaxial acrofacial dysostosis (Ng et al. 2010; Roach et al. 2010). This variant was not identified in 237 control individuals but is reported at a frequency of 0.000180 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies performed by Fang et al. (2012) suggested the p.Gly152Arg variant affects protein expression or turnover. In addition, Rainger et al. (2012) determined that the variant enzyme shows reduced activity compared to wild type, although a larger effect was observed using a complementation assay than an in vitro assay of enzyme activity. The evidence for this variant is limited. The p.Gly152Arg variant is thus classified as of a variant of unknown significance but suspicious for pathogenicity for postaxial acrofacial dysostosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Uncertain:1

Jun 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 152 of the DHODH protein (p.Gly152Arg). This variant is present in population databases (rs267606766, gnomAD 0.01%). This missense change has been observed in individual(s) with Miller syndrome (PMID: 19915526, 20220176). It has also been observed to segregate with disease in related individuals. This variant is also known as chr16:70608443 G>R. ClinVar contains an entry for this variant (Variation ID: 16803). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DHODH function (PMID: 22692683, 22967083). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Benign

0.83

DEOGEN2

Pathogenic

0.91

.;D;D

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.7

.;H;.

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-7.8

.;D;.

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

1.0

MutPred

0.98

Gain of MoRF binding (P = 0.0097);Gain of MoRF binding (P = 0.0097);.;

MVP

0.99

MPC

0.82

ClinPred

0.96

GERP RS

5.8

Varity_R

0.98

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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