Variant 3-114128883-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000796.6(DRD3):c.1036T>C(p.Phe346Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000035 in 1,455,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

DRD3
NM_000796.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32

Variant links:

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]

DRD3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DRD3	NM_000796.6 linkuse as main transcript	c.1036T>C	p.Phe346Leu	missense_variant	7/7	ENST00000383673.5	NP_000787.2	P35462-1X5D2G4A8K8E4
DRD3	NM_001282563.2 linkuse as main transcript	c.1036T>C	p.Phe346Leu	missense_variant	8/8		NP_001269492.1	P35462-1X5D2G4A8K8E4
DRD3	NM_001290809.1 linkuse as main transcript	c.1036T>C	p.Phe346Leu	missense_variant	8/8		NP_001277738.1	P35462-1X5D2G4A8K8E4A1A4V4
DRD3	NM_033663.6 linkuse as main transcript	c.937T>C	p.Phe313Leu	missense_variant	8/8		NP_387512.3	P35462-3E9PCM4A8K8E4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DRD3	ENST00000383673.5 linkuse as main transcript	c.1036T>C	p.Phe346Leu	missense_variant	7/7	1	NM_000796.6	ENSP00000373169.2		P35462-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000204

AC:

AN:

245358

Hom.:

AF XY:

0.0000226

AC XY:

AN XY:

132664

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000449

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000350

AC:

AN:

1455430

Hom.:

Cov.:

AF XY:

0.0000318

AC XY:

AN XY:

723700

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000442

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000313

Hom.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2024

The c.1036T>C (p.F346L) alteration is located in exon 7 (coding exon 6) of the DRD3 gene. This alteration results from a T to C substitution at nucleotide position 1036, causing the phenylalanine (F) at amino acid position 346 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;.;D;D

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.93

D;D;D;D

MetaSVM

Uncertain

0.13

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.0

D;D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.028

D;D;D;D

Sift4G

Uncertain

0.018

D;D;D;D

Polyphen

1.0

.;.;D;.

Vest4

0.87

MutPred

0.80

Loss of catalytic residue at F346 (P = 0.1129);Loss of catalytic residue at F346 (P = 0.1129);.;Loss of catalytic residue at F346 (P = 0.1129);

MVP

0.92

MPC

1.3

ClinPred

0.98

GERP RS

5.4

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over