dbSNP rs1800443: DRD4:p.Val194Asp (chr11-639830-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM2PP3_ModerateBS2

The NM_000797.4(DRD4):c.581T>A(p.Val194Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000349 in 1,434,408 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V194G) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

DRD4
NM_000797.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.43

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.864

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRD4	NM_000797.4 link	c.581T>A	p.Val194Asp	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>A	p.Val194Asp	missense_variant	Exon 3 of 4	1	NM_000797.4	ENSP00000176183.5		P21917
DRD4	ENST00000528733.1 link	n.*37T>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000349

AC:

AN:

1434408

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32186

American (AMR)

AF:

0.00

AC:

AN:

43776

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25714

East Asian (EAS)

AF:

0.00

AC:

AN:

38930

South Asian (SAS)

AF:

0.00

AC:

AN:

84940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5342

European-Non Finnish (NFE)

AF:

0.00000452

AC:

AN:

1106060

Other (OTH)

AF:

0.00

AC:

AN:

59654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Benign

0.84

Eigen

Benign

0.035

Eigen_PC

Benign

-0.086

FATHMM_MKL

Uncertain

0.88

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

-0.22

PhyloP100

5.4

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Vest4

0.79

MutPred

0.70

Gain of phosphorylation at Y192 (P = 0.099);

MVP

0.83

MPC

0.46

ClinPred

0.90

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.5

gMVP

0.91

Mutation Taster

=39/61

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over