NM_001361.5:c.454G>A

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

15
2
2

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

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]

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
DHODHNM_001361.5 linkc.454G>A p.Gly152Arg missense_variant Exon 4 of 9 ENST00000219240.9 NP_001352.2 Q02127
DHODHXM_047433674.1 linkc.370G>A p.Gly124Arg missense_variant Exon 4 of 9 XP_047289630.1
DHODHXM_005255829.5 linkc.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
DHODHENST00000219240.9 linkc.454G>A p.Gly152Arg missense_variant Exon 4 of 9 1 NM_001361.5 ENSP00000219240.4 Q02127

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152018
Hom.:
0
Cov.:
32
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:
19
AN:
249544
Hom.:
0
AF XY:
0.0000812
AC XY:
11
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.:
0
Cov.:
32
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:
8
AN:
152018
Hom.:
0
Cov.:
32
AF XY:
0.0000539
AC XY:
4
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.:
0
Bravo
AF:
0.0000567
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000120
AC:
1
ExAC
AF:
0.0000993
AC:
12
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Miller syndrome Pathogenic:1
Jan 01, 2010
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

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
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
30
DANN
Benign
0.83
DEOGEN2
Pathogenic
0.91
.;D;D
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.7
.;H;.
PrimateAI
Uncertain
0.62
T
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
D
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.

Other links and lift over

dbSNP: rs267606766; hg19: chr16-72050942; API