rs375174980

Variant names:

• chr16-72012168-G-A
• rs375174980
• NM_001361.5:c.140G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001361.5(DHODH):​c.140G>A​(p.Gly47Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000496 in 1,614,136 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: DHODH NM_001361.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.53

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10173297).
• BP6: Variant 16-72012168-G-A is Benign according to our data. Variant chr16-72012168-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2056660.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHODH	NM_001361.5	c.140G>A	p.Gly47Glu	missense_variant	Exon 2 of 9	ENST00000219240.9	NP_001352.2
DHODH	XM_047433674.1	c.56G>A	p.Gly19Glu	missense_variant	Exon 2 of 9		XP_047289630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHODH	ENST00000219240.9	c.140G>A	p.Gly47Glu	missense_variant	Exon 2 of 9	1	NM_001361.5	ENSP00000219240.4

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152138 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.0000360 AC: 9 AN: 249704 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135452

Gnomad AFR exome AF: 0.0000644

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000988

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.0000371 AC XY: 27 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152256 Hom.: 1 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74424

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000169 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.140G>A (p.G47E) alteration is located in exon 2 (coding exon 2) of the DHODH gene. This alteration results from a G to A substitution at nucleotide position 140, causing the glycine (G) at amino acid position 47 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Jul 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.068	.;T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.6	.;L;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.56	.;N;.
REVEL	Benign	0.26
Sift	Benign	0.32	.;T;.
Sift4G	Benign	0.95	T;T;T
Polyphen		0.0030	.;B;.
Vest4		0.32
MutPred		0.49		Gain of disorder (P = 0.0516);Gain of disorder (P = 0.0516);.;
MVP		0.90
MPC		0.24
ClinPred		0.057	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs375174980; hg19: chr16-72046067; COSMIC: COSV99537054; COSMIC: COSV99537054;