rs148523165

chr16-72021179-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001361.5(DHODH):c.573G>A(p.Ala191=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,609,634 control chromosomes in the GnomAD database, including 144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (137 hom.)
• Consequence: DHODH NM_001361.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.311

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 16-72021179-G-A is Benign according to our data. Variant chr16-72021179-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.311 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHODH	NM_001361.5	c.573G>A	p.Ala191=	synonymous_variant	5/9	ENST00000219240.9
DHODH	XM_047433674.1	c.489G>A	p.Ala163=	synonymous_variant	5/9
DHODH	XM_005255829.5	c.144G>A	p.Ala48=	synonymous_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHODH	ENST00000219240.9	c.573G>A	p.Ala191=	synonymous_variant	5/9	1	NM_001361.5	P3

Frequencies

GnomAD3 genomes AF: 0.00865 AC: 1317 AN: 152212 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00491

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00801 AC: 1911 AN: 238504 Hom.: 18 AF XY: 0.00803 AC XY: 1041 AN XY: 129584

Gnomad AFR exome AF: 0.00312

Gnomad AMR exome AF: 0.00420

Gnomad ASJ exome AF: 0.00754

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000919

Gnomad FIN exome AF: 0.00979

Gnomad NFE exome AF: 0.0128

Gnomad OTH exome AF: 0.00705

GnomAD4 exome AF: 0.0117 AC: 17040 AN: 1457304 Hom.: 137 Cov.: 33 AF XY: 0.0115 AC XY: 8344 AN XY: 724536

Gnomad4 AFR exome AF: 0.00189

Gnomad4 AMR exome AF: 0.00428

Gnomad4 ASJ exome AF: 0.00781

Gnomad4 EAS exome AF: 0.0000759

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.00951

Gnomad4 NFE exome AF: 0.0138

Gnomad4 OTH exome AF: 0.0113

GnomAD4 genome AF: 0.00864 AC: 1316 AN: 152330 Hom.: 7 Cov.: 32 AF XY: 0.00840 AC XY: 626 AN XY: 74496

Gnomad4 AFR AF: 0.00269

Gnomad4 AMR AF: 0.00490

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0115 Hom.: 7

Bravo AF: 0.00764

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	DHODH: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Miller syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	4.4
Dann	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs148523165; hg19: chr16-72055078; COSMIC: COSV54662956; COSMIC: COSV54662956;