rs374359731

Variant names:

• chr11-637443-G-A
• rs374359731
• NM_000797.4:c.139G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-637443-G-A
• chr11-637443-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000797.4(DRD4):​c.139G>A​(p.Ala47Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000515 in 1,532,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: DRD4 NM_000797.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.321
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042067915).
• BS2: High AC in GnomAd4 at 13 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.139G>A	p.Ala47Thr	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.139G>A	p.Ala47Thr	missense	Exon 1 of 4	ENSP00000176183.5	P21917

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152038 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000177

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000380 AC: 5 AN: 131426 AF XY: 0.0000140

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: 0.000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000478 AC: 66 AN: 1380872 Hom.: 0 Cov.: 32 AF XY: 0.0000528 AC XY: 36 AN XY: 681292

African (AFR) AF: 0.00 AC: 0 AN: 31368

American (AMR) AF: 0.00 AC: 0 AN: 35608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25068

East Asian (EAS) AF: 0.00 AC: 0 AN: 35616

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 79088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4878

European-Non Finnish (NFE) AF: 0.0000585 AC: 63 AN: 1077656

Other (OTH) AF: 0.0000173 AC: 1 AN: 57684

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152038 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74258

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000324 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000261 AC: 2

ExAC AF: 0.0000355 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.014	N
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.99	T
PhyloP100		0.32
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.040
Sift	Uncertain	0.025	D
Sift4G	Benign	0.44	T
Vest4		0.22
MVP		0.085
MPC		0.28
ClinPred		0.058	T
GERP RS		-2.2
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
gMVP		0.25
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs374359731; hg19: chr11-637443;