16-72008779-C-A

Variant names:

• chr16-72008779-C-A
• rs944548885
• NM_001361.5:c.15C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001361.5(DHODH):​c.15C>A​(p.His5Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,551,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H5R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 35)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DHODH NM_001361.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.03
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• postaxial acrofacial dysostosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000294600 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023801118).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001361.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHODH	NM_001361.5	MANE Select	c.15C>A	p.His5Gln	missense	Exon 1 of 9	NP_001352.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHODH	ENST00000219240.9	TSL:1 MANE Select	c.15C>A	p.His5Gln	missense	Exon 1 of 9	ENSP00000219240.4	Q02127
	DHODH	ENST00000894311.1		c.15C>A	p.His5Gln	missense	Exon 1 of 11	ENSP00000564370.1
	DHODH	ENST00000894313.1		c.15C>A	p.His5Gln	missense	Exon 1 of 9	ENSP00000564372.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000644 AC: 1 AN: 155242 AF XY: 0.0000122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1399600 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690316

African (AFR) AF: 0.00 AC: 0 AN: 31618

American (AMR) AF: 0.0000280 AC: 1 AN: 35716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35756

South Asian (SAS) AF: 0.00 AC: 0 AN: 79242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079050

Other (OTH) AF: 0.00 AC: 0 AN: 58046

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 74346

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	0.31
DANN	Benign	0.83
DEOGEN2	Benign	0.057	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-1.0	N
PhyloP100		-3.0
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.75	N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.084
MutPred		0.16		Gain of helix (P = 0.0425)
MVP		0.50
MPC		0.19
ClinPred		0.083	T
GERP RS		-7.7
PromoterAI		0.28	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.055
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs944548885; hg19: chr16-72042678;