chr11-637408-C-A

Variant names:

• chr11-637408-C-A
• rs767779176
• NM_000797.4:c.104C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BS2

The NM_000797.4(DRD4):​c.104C>A​(p.Ala35Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,342,878 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign 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. A35V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: DRD4 NM_000797.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.436
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 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.104C>A	p.Ala35Glu	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.104C>A	p.Ala35Glu	missense	Exon 1 of 4	ENSP00000176183.5	P21917

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000314 AC: 3 AN: 95680 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000143

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000372 AC: 5 AN: 1342878 Hom.: 0 Cov.: 32 AF XY: 0.00000152 AC XY: 1 AN XY: 660020

African (AFR) AF: 0.00 AC: 0 AN: 27848

American (AMR) AF: 0.000123 AC: 4 AN: 32494

Ashkenazi Jewish (ASJ) AF: 0.0000436 AC: 1 AN: 22938

East Asian (EAS) AF: 0.00 AC: 0 AN: 32084

South Asian (SAS) AF: 0.00 AC: 0 AN: 73392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4048

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061406

Other (OTH) AF: 0.00 AC: 0 AN: 55978

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Uncertain	0.98
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.21	N
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.86	T
PhyloP100		-0.44
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.20
Sift	Benign	0.27	T
Sift4G	Benign	0.11	T
Vest4		0.45
MutPred		0.38		Gain of loop (P = 0.1069)
MVP		0.77
MPC		0.33
ClinPred		0.50	D
GERP RS		0.40
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		4.2
gMVP		0.46
Mutation Taster		=66/34	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: rs767779176; hg19: chr11-637408;