rs3213422

Variant names:

• chr16-72008783-A-C
• rs3213422
• NM_001361.5:c.19A>C

Your query was ambiguous. Multiple possible variants found:

• chr16-72008783-A-C
• chr16-72008783-A-G
• chr16-72008783-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001361.5(DHODH):​c.19A>C​(p.Lys7Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 1,551,792 control chromosomes in the GnomAD database, including 214,917 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22447 hom., cov: 34)
  • Exomes 𝑓: 0.52 (192470 hom.)
• Consequence: DHODH NM_001361.5 missense, splice_region
• Scores: Splicing: ADA: 0.0003165
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.21
• Publications: 78 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5988757E-6).
• BP6: Variant 16-72008783-A-C is Benign according to our data. Variant chr16-72008783-A-C is described in ClinVar as Benign. ClinVar VariationId is 128895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

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.19A>C	p.Lys7Gln	missense splice_region	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.19A>C	p.Lys7Gln	missense splice_region	Exon 1 of 9	ENSP00000219240.4	Q02127
	DHODH	ENST00000894311.1		c.19A>C	p.Lys7Gln	missense splice_region	Exon 1 of 11	ENSP00000564370.1
	DHODH	ENST00000894313.1		c.19A>C	p.Lys7Gln	missense splice_region	Exon 1 of 9	ENSP00000564372.1

Frequencies

GnomAD3 genomes AF: 0.540 AC: 82091 AN: 152028 Hom.: 22430 Cov.: 34

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.634

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.525

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.505

GnomAD2 exomes AF: 0.554 AC: 86023 AN: 155404 AF XY: 0.542

Gnomad AFR exome AF: 0.545

Gnomad AMR exome AF: 0.679

Gnomad ASJ exome AF: 0.519

Gnomad EAS exome AF: 0.778

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.507

Gnomad OTH exome AF: 0.503

GnomAD4 exome AF: 0.522 AC: 730105 AN: 1399646 Hom.: 192470 Cov.: 68 AF XY: 0.519 AC XY: 358109 AN XY: 690350

African (AFR) AF: 0.541 AC: 17121 AN: 31624

American (AMR) AF: 0.670 AC: 23935 AN: 35720

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 13008 AN: 25180

East Asian (EAS) AF: 0.712 AC: 25475 AN: 35760

South Asian (SAS) AF: 0.465 AC: 36888 AN: 79256

European-Finnish (FIN) AF: 0.529 AC: 26087 AN: 49352

Middle Eastern (MID) AF: 0.382 AC: 2148 AN: 5622

European-Non Finnish (NFE) AF: 0.514 AC: 555089 AN: 1079084

Other (OTH) AF: 0.523 AC: 30354 AN: 58048

GnomAD4 genome AF: 0.540 AC: 82156 AN: 152146 Hom.: 22447 Cov.: 34 AF XY: 0.545 AC XY: 40568 AN XY: 74382

African (AFR) AF: 0.547 AC: 22693 AN: 41524

American (AMR) AF: 0.616 AC: 9430 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 1821 AN: 3470

East Asian (EAS) AF: 0.755 AC: 3903 AN: 5170

South Asian (SAS) AF: 0.473 AC: 2278 AN: 4818

European-Finnish (FIN) AF: 0.540 AC: 5713 AN: 10584

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.509 AC: 34568 AN: 67962

Other (OTH) AF: 0.506 AC: 1069 AN: 2114

Alfa AF: 0.520 Hom.: 94465

Bravo AF: 0.550

TwinsUK AF: 0.519 AC: 1924

ALSPAC AF: 0.513 AC: 1976

ESP6500AA AF: 0.585 AC: 2268

ESP6500EA AF: 0.525 AC: 4234

ExAC AF: 0.409 AC: 29023

Asia WGS AF: 0.594 AC: 2064 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Miller syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0000026	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.37	N
PhyloP100		1.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.36
Sift	Benign	0.12	T
Sift4G	Benign	0.26	T
Polyphen		0.0020	B
Vest4		0.065
MPC		0.20
ClinPred		0.019	T
GERP RS		2.9
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.47
Mutation Taster		=81/19	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.0
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: rs3213422; hg19: chr16-72042682; COSMIC: COSV54662830; COSMIC: COSV54662830;