dbSNP rs189482961: DRD4:p.Gly11Arg (chr11-637335-G-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000797.4(DRD4):c.31G>C(p.Gly11Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,263,252 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0080 ( 11 hom., cov: 32)

Exomes 𝑓: 0.013 ( 109 hom. )

Consequence

DRD4
NM_000797.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.37

Publications

6 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011060178).

BP6

Variant 11-637335-G-C is Benign according to our data. Variant chr11-637335-G-C is described in ClinVar as Benign. ClinVar VariationId is 787592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 1208 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000797.4. 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
	DRD4	NM_000797.4	MANE Select	c.31G>C	p.Gly11Arg	missense	Exon 1 of 4	NP_000788.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRD4	ENST00000176183.6	TSL:1 MANE Select	c.31G>C	p.Gly11Arg	missense	Exon 1 of 4	ENSP00000176183.5	P21917

Frequencies

GnomAD3 genomes

AF:

0.00801

AC:

1208

AN:

150758

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00238

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00337

Gnomad ASJ

AF:

0.00434

Gnomad EAS

AF:

0.000391

Gnomad SAS

AF:

0.000832

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0134

Gnomad OTH

AF:

0.00483

GnomAD2 exomes

AF:

0.00365

AC:

AN:

2738

AF XY:

0.00323

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00657

Gnomad OTH exome

AF:

0.0125

GnomAD4 exome

AF:

0.0127

AC:

14106

AN:

1112386

Hom.:

109

Cov.:

AF XY:

0.0126

AC XY:

6720

AN XY:

532366

show subpopulations

African (AFR)

AF:

0.000899

AC:

AN:

22236

American (AMR)

AF:

0.00349

AC:

AN:

8026

Ashkenazi Jewish (ASJ)

AF:

0.00241

AC:

AN:

14088

East Asian (EAS)

AF:

0.0000405

AC:

AN:

24680

South Asian (SAS)

AF:

0.00213

AC:

AN:

30002

European-Finnish (FIN)

AF:

0.0116

AC:

273

AN:

23578

Middle Eastern (MID)

AF:

0.00167

AC:

AN:

2990

European-Non Finnish (NFE)

AF:

0.0140

AC:

13219

AN:

942144

Other (OTH)

AF:

0.0103

AC:

462

AN:

44642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

719

1438

2158

2877

3596

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

586

1172

1758

2344

2930

<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:

0.00801

AC:

1208

AN:

150866

Hom.:

Cov.:

AF XY:

0.00764

AC XY:

563

AN XY:

73730

show subpopulations

African (AFR)

AF:

0.00237

AC:

AN:

41290

American (AMR)

AF:

0.00337

AC:

AN:

15150

Ashkenazi Jewish (ASJ)

AF:

0.00434

AC:

AN:

3460

East Asian (EAS)

AF:

0.000392

AC:

AN:

5098

South Asian (SAS)

AF:

0.000833

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.0117

AC:

120

AN:

10216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0134

AC:

908

AN:

67566

Other (OTH)

AF:

0.00478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00494

Hom.:

Bravo

AF:

0.00706

ExAC

AF:

0.000566

AC:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

DRD4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

7.4

(source)

DANN

Benign

0.87

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.023

M_CAP

Pathogenic

0.76

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.1

PhyloP100

-1.4

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.52

REVEL

Benign

0.049

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0

Vest4

0.16

MutPred

0.17

Gain of MoRF binding (P = 0.0032)

MVP

0.45

MPC

0.34

ClinPred

0.068

GERP RS

-2.9

PromoterAI

-0.013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

gMVP

0.55

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over