16-72012058-CCAGGATGCTGTGATCA-C

Variant names:

• chr16-72012058-CCAGGATGCTGTGATCA-C
• NM_001361.5:c.31_46delCAGGATGCTGTGATCA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001361.5(DHODH):​c.31_46delCAGGATGCTGTGATCA​(p.Gln11SerfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHODH NM_001361.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.49

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_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.974 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-72012058-CCAGGATGCTGTGATCA-C is Pathogenic according to our data. Variant chr16-72012058-CCAGGATGCTGTGATCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 3667173.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHODH	NM_001361.5	c.31_46delCAGGATGCTGTGATCA	p.Gln11SerfsTer13	frameshift_variant	Exon 2 of 9	ENST00000219240.9	NP_001352.2
DHODH	XM_047433674.1	c.-54_-39delCAGGATGCTGTGATCA		5_prime_UTR_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.31_46delCAGGATGCTGTGATCA	p.Gln11SerfsTer13	frameshift_variant	Exon 2 of 9	1	NM_001361.5	ENSP00000219240.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Mar 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln11Serfs*13) in the DHODH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DHODH are known to be pathogenic (PMID: 22692683, 22967083). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DHODH-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-72045957;