11-637426-G-A

Variant names:

• chr11-637426-G-A
• rs780467485
• NM_000797.4:c.122G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000797.4(DRD4):​c.122G>A​(p.Gly41Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,374,898 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. G41V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: DRD4 NM_000797.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.973
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

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.122G>A	p.Gly41Asp	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.122G>A	p.Gly41Asp	missense	Exon 1 of 4	ENSP00000176183.5	P21917

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1374898 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 677800

African (AFR) AF: 0.00 AC: 0 AN: 30690

American (AMR) AF: 0.00 AC: 0 AN: 35438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24868

East Asian (EAS) AF: 0.00 AC: 0 AN: 35076

South Asian (SAS) AF: 0.00 AC: 0 AN: 78654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4306

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1074928

Other (OTH) AF: 0.00 AC: 0 AN: 57378

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.31	T
PhyloP100		0.97
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.54
Sift	Benign	0.075	T
Sift4G	Benign	0.069	T
Vest4		0.62
MutPred		0.52		Loss of catalytic residue at V42 (P = 0.2345)
MVP		0.75
MPC		0.37
ClinPred		0.95	D
GERP RS		2.4
PromoterAI		0.040	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.5
gMVP		0.85
Mutation Taster		=19/81	disease causing

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: rs780467485; hg19: chr11-637426;