rs6280

Variant names:

• chr3-114171968-C-T
• rs6280
• NM_000796.6:c.25G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000796.6(DRD3):​c.25G>A​(p.Gly9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.642 in 1,496,244 control chromosomes in the GnomAD database, including 316,020 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (25265 hom., cov: 32)
  • Exomes 𝑓: 0.65 (290755 hom.)
• Consequence: DRD3 NM_000796.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:2
• Conservation: PhyloP100: -0.471

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.230764E-6).
• BP6: Variant 3-114171968-C-T is Benign according to our data. Variant chr3-114171968-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 16770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRD3	NM_000796.6	c.25G>A	p.Gly9Ser	missense_variant	Exon 2 of 7	ENST00000383673.5	NP_000787.2
DRD3	NM_001282563.2	c.25G>A	p.Gly9Ser	missense_variant	Exon 3 of 8		NP_001269492.1
DRD3	NM_001290809.1	c.25G>A	p.Gly9Ser	missense_variant	Exon 3 of 8		NP_001277738.1
DRD3	NM_033663.6	c.25G>A	p.Gly9Ser	missense_variant	Exon 2 of 8		NP_387512.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRD3	ENST00000383673.5	c.25G>A	p.Gly9Ser	missense_variant	Exon 2 of 7	1	NM_000796.6	ENSP00000373169.2

Frequencies

GnomAD3 genomes AF: 0.547 AC: 83156 AN: 151970 Hom.: 25266 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.648

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.707

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.662

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.673

Gnomad OTH AF: 0.588

GnomAD3 exomes AF: 0.628 AC: 95572 AN: 152300 Hom.: 30801 AF XY: 0.634 AC XY: 51824 AN XY: 81692

Gnomad AFR exome AF: 0.263

Gnomad AMR exome AF: 0.549

Gnomad ASJ exome AF: 0.726

Gnomad EAS exome AF: 0.696

Gnomad SAS exome AF: 0.592

Gnomad FIN exome AF: 0.674

Gnomad NFE exome AF: 0.680

Gnomad OTH exome AF: 0.662

GnomAD4 exome AF: 0.653 AC: 877824 AN: 1344156 Hom.: 290755 Cov.: 63 AF XY: 0.653 AC XY: 429752 AN XY: 658204

Gnomad4 AFR exome AF: 0.245

Gnomad4 AMR exome AF: 0.547

Gnomad4 ASJ exome AF: 0.714

Gnomad4 EAS exome AF: 0.714

Gnomad4 SAS exome AF: 0.586

Gnomad4 FIN exome AF: 0.675

Gnomad4 NFE exome AF: 0.669

Gnomad4 OTH exome AF: 0.630

GnomAD4 genome AF: 0.547 AC: 83186 AN: 152088 Hom.: 25265 Cov.: 32 AF XY: 0.547 AC XY: 40624 AN XY: 74316

Gnomad4 AFR AF: 0.269

Gnomad4 AMR AF: 0.547

Gnomad4 ASJ AF: 0.707

Gnomad4 EAS AF: 0.698

Gnomad4 SAS AF: 0.591

Gnomad4 FIN AF: 0.662

Gnomad4 NFE AF: 0.673

Gnomad4 OTH AF: 0.587

Alfa AF: 0.651 Hom.: 80419

Bravo AF: 0.528

TwinsUK AF: 0.662 AC: 2454

ALSPAC AF: 0.662 AC: 2551

ESP6500AA AF: 0.276 AC: 1216

ESP6500EA AF: 0.666 AC: 5723

ExAC AF: 0.585 AC: 70275

Asia WGS AF: 0.615 AC: 2140 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 09, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

DRD3-related disorder Benign:1

Aug 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Tremor, hereditary essential, 1 Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Schizophrenia, susceptibility to Other:1

Mar 06, 2007

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Essential tremor, susceptibility to Other:1

Mar 06, 2007

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.082
DANN	Benign	0.82
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.41	.;.;T;T
MetaRNN	Benign	0.0000022	T;T;T;T
MetaSVM	Benign	-0.93	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.98	N;N;N;N
REVEL	Benign	0.033
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;.;B;.
Vest4		0.022
MPC		0.37
ClinPred		0.00050	T
GERP RS		-1.5
gMVP		0.29

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: rs6280; hg19: chr3-113890815; COSMIC: COSV55678322;