Genetic Variant DRD4:p.Val194Gly (chr11-639830-T-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000797.4(DRD4):c.581T>G(p.Val194Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00294 in 1,585,222 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.016 ( 53 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 54 hom. )

Consequence

DRD4
NM_000797.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 5.43

Publications

21 publications found

Variant links:

Genes affected

DRD4 (HGNC:3025): (dopamine receptor D4) This gene encodes the D4 subtype of the dopamine receptor. The D4 subtype is a G-protein coupled receptor which inhibits adenylyl cyclase. It is a target for drugs which treat schizophrenia and Parkinson disease. Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder, and the personality trait of novelty seeking. This gene contains a polymorphic number (2-10 copies) of tandem 48 nt repeats; the sequence shown contains four repeats. [provided by RefSeq, Jul 2008]

DRD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008655846).

BP6

Variant 11-639830-T-G is Benign according to our data. Variant chr11-639830-T-G is described in ClinVar as Benign. ClinVar VariationId is 16768.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRD4	NM_000797.4 link	c.581T>G	p.Val194Gly	missense_variant	Exon 3 of 4	ENST00000176183.6	NP_000788.2	P21917

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRD4	ENST00000176183.6 link	c.581T>G	p.Val194Gly	missense_variant	Exon 3 of 4	1	NM_000797.4	ENSP00000176183.5		P21917
DRD4	ENST00000528733.1 link	n.*37T>G		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0159

AC:

2402

AN:

150716

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0542

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00725

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000341

Gnomad OTH

AF:

0.0145

GnomAD2 exomes

AF:

0.00374

AC:

849

AN:

227194

AF XY:

0.00253

show subpopulations

Gnomad AFR exome

AF:

0.0521

Gnomad AMR exome

AF:

0.00216

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000197

Gnomad OTH exome

AF:

0.00193

GnomAD4 exome

AF:

0.00157

AC:

2254

AN:

1434398

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

987

AN XY:

714198

show subpopulations

African (AFR)

AF:

0.0524

AC:

1685

AN:

32176

American (AMR)

AF:

0.00279

AC:

122

AN:

43776

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25714

East Asian (EAS)

AF:

0.00

AC:

AN:

38930

South Asian (SAS)

AF:

0.000118

AC:

AN:

84940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37806

Middle Eastern (MID)

AF:

0.00168

AC:

AN:

5342

European-Non Finnish (NFE)

AF:

0.000192

AC:

212

AN:

1106060

Other (OTH)

AF:

0.00362

AC:

216

AN:

59654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

124

248

373

497

621

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0160

AC:

2406

AN:

150824

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1182

AN XY:

73656

show subpopulations

African (AFR)

AF:

0.0542

AC:

2242

AN:

41380

American (AMR)

AF:

0.00724

AC:

110

AN:

15188

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000341

AC:

AN:

67512

Other (OTH)

AF:

0.0143

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

120

240

361

481

601

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00489

Hom.:

ESP6500AA

AF:

0.0488

AC:

215

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00447

AC:

536

Asia WGS

AF:

0.00121

AC:

AN:

3332

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

DRD4 POLYMORPHISM

Benign:1

Jan 22, 1996

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

(source)

DANN

Benign

0.88

Eigen

Benign

-0.057

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.89

MetaRNN

Benign

0.0087

MetaSVM

Benign

-0.76

PhyloP100

5.4

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.58

MVP

0.79

MPC

0.37

ClinPred

0.14

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.5

gMVP

0.79

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over