dbSNP rs146562378: DRD4:p.Ala78Thr (chr11-637536-G-A) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000797.4(DRD4):c.232G>A(p.Ala78Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,564,100 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

DRD4
NM_000797.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.55

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 made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010498613).

BP6

Variant 11-637536-G-A is Benign according to our data. Variant chr11-637536-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3039973.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 320 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRD4	NM_000797.4 link	c.232G>A	p.Ala78Thr	missense_variant	Exon 1 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.232G>A	p.Ala78Thr	missense_variant	Exon 1 of 4	1	NM_000797.4	ENSP00000176183.5		P21917

Frequencies

GnomAD3 genomes

AF:

0.00210

AC:

319

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00758

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000497

AC:

AN:

171114

Hom.:

AF XY:

0.000334

AC XY:

AN XY:

92706

show subpopulations

Gnomad AFR exome

AF:

0.00789

Gnomad AMR exome

AF:

0.000111

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000215

AC:

303

AN:

1411834

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

143

AN XY:

698878

show subpopulations

Gnomad4 AFR exome

AF:

0.00848

Gnomad4 AMR exome

AF:

0.0000785

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:

9.16e-7

Gnomad4 OTH exome

AF:

0.000358

GnomAD4 genome

AF:

0.00210

AC:

320

AN:

152266

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00758

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.00230

ESP6500AA

AF:

0.00734

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000530

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

DRD4-related disorder

Benign:1

Oct 02, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.95

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.1

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.72

REVEL

Benign

0.030

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.037

Vest4

0.29

MVP

0.32

MPC

0.28

ClinPred

0.037

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

gMVP

0.48

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

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