rs746592271

Variant names:

• chr3-114128747-C-T
• rs746592271
• NM_000796.6:c.1172G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-114128747-C-T
• chr3-114128747-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000796.6(DRD3):​c.1172G>A​(p.Arg391Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,608,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: DRD3 NM_000796.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 2 publications found

Genes affected

DRD3 (HGNC:3024): (dopamine receptor D3) This gene encodes the D3 subtype of the five (D1-D5) dopamine receptors. The activity of the D3 subtype receptor is mediated by G proteins which inhibit adenylyl cyclase. This receptor is localized to the limbic areas of the brain, which are associated with cognitive, emotional, and endocrine functions. Genetic variation in this gene may be associated with susceptibility to hereditary essential tremor 1. Alternative splicing of this gene results in transcript variants encoding different isoforms, although some variants may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000796.6. 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
	DRD3	NM_000796.6	MANE Select	c.1172G>A	p.Arg391Gln	missense	Exon 7 of 7	NP_000787.2	X5D2G4
	DRD3	NM_001282563.2		c.1172G>A	p.Arg391Gln	missense	Exon 8 of 8	NP_001269492.1	P35462-1
	DRD3	NM_001290809.1		c.1172G>A	p.Arg391Gln	missense	Exon 8 of 8	NP_001277738.1	X5D2G4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRD3	ENST00000383673.5	TSL:1 MANE Select	c.1172G>A	p.Arg391Gln	missense	Exon 7 of 7	ENSP00000373169.2	P35462-1
	DRD3	ENST00000467632.5	TSL:1	c.1172G>A	p.Arg391Gln	missense	Exon 8 of 8	ENSP00000420662.1	P35462-1
	DRD3	ENST00000460779.5	TSL:2	c.1172G>A	p.Arg391Gln	missense	Exon 8 of 8	ENSP00000419402.1	P35462-1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000891 AC: 22 AN: 246850 AF XY: 0.0000975

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000504

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000206 AC: 30 AN: 1456118 Hom.: 0 Cov.: 30 AF XY: 0.0000262 AC XY: 19 AN XY: 724024

African (AFR) AF: 0.0000300 AC: 1 AN: 33288

American (AMR) AF: 0.000388 AC: 17 AN: 43848

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25812

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39614

South Asian (SAS) AF: 0.0000820 AC: 7 AN: 85334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53292

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1109052

Other (OTH) AF: 0.00 AC: 0 AN: 60146

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152012 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74244

African (AFR) AF: 0.0000242 AC: 1 AN: 41382

American (AMR) AF: 0.0000656 AC: 1 AN: 15254

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000741 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.65	T
PhyloP100		7.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.88		Loss of MoRF binding (P = 0.0274)
MVP		0.91
MPC		1.3
ClinPred		0.92	D
GERP RS		5.4
gMVP		0.94
Mutation Taster		=23/77	disease causing

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: rs746592271; hg19: chr3-113847594; COSMIC: COSV55680182;