rs148523165

Variant names:

• chr16-72021179-G-A
• rs148523165
• NM_001361.5:c.573G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001361.5(DHODH):​c.573G>A​(p.Ala191Ala) 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:5
• Conservation: PhyloP100: -0.311
• Publications: 5 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)

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 GnomAd4 at 7 AR gene

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.573G>A	p.Ala191Ala	synonymous	Exon 5 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.573G>A	p.Ala191Ala	synonymous	Exon 5 of 9	ENSP00000219240.4	Q02127
	DHODH	ENST00000894311.1		c.759G>A	p.Ala253Ala	synonymous	Exon 7 of 11	ENSP00000564370.1
	DHODH	ENST00000894313.1		c.570G>A	p.Ala190Ala	synonymous	Exon 5 of 9	ENSP00000564372.1

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

GnomAD2 exomes AF: 0.00801 AC: 1911 AN: 238504 AF XY: 0.00803

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 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

African (AFR) AF: 0.00189 AC: 63 AN: 33410

American (AMR) AF: 0.00428 AC: 189 AN: 44140

Ashkenazi Jewish (ASJ) AF: 0.00781 AC: 203 AN: 26008

East Asian (EAS) AF: 0.0000759 AC: 3 AN: 39506

South Asian (SAS) AF: 0.00108 AC: 92 AN: 85318

European-Finnish (FIN) AF: 0.00951 AC: 503 AN: 52900

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5760

European-Non Finnish (NFE) AF: 0.0138 AC: 15301 AN: 1110068

Other (OTH) AF: 0.0113 AC: 679 AN: 60194

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

African (AFR) AF: 0.00269 AC: 112 AN: 41570

American (AMR) AF: 0.00490 AC: 75 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4834

European-Finnish (FIN) AF: 0.0101 AC: 107 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0141 AC: 962 AN: 68032

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0107 Hom.: 11

Bravo AF: 0.00764

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Miller syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	4.4
DANN	Benign	0.74
PhyloP100		-0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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