11-637534-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_000797.4(DRD4):​c.230C>T​(p.Ala77Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000556 in 1,563,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

DRD4
NM_000797.4 missense

Scores

7
7
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.44
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.896
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DRD4NM_000797.4 linkc.230C>T p.Ala77Val 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
DRD4ENST00000176183.6 linkc.230C>T p.Ala77Val missense_variant Exon 1 of 4 1 NM_000797.4 ENSP00000176183.5 P21917

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152062
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000409
AC:
7
AN:
170944
Hom.:
0
AF XY:
0.0000108
AC XY:
1
AN XY:
92616
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000371
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:
0.0000697
Gnomad OTH exome
AF:
0.000212
GnomAD4 exome
AF:
0.0000574
AC:
81
AN:
1411468
Hom.:
0
Cov.:
32
AF XY:
0.0000558
AC XY:
39
AN XY:
698684
show subpopulations
Gnomad4 AFR exome
AF:
0.0000307
Gnomad4 AMR exome
AF:
0.0000523
Gnomad4 ASJ exome
AF:
0.0000394
Gnomad4 EAS exome
AF:
0.0000268
Gnomad4 SAS exome
AF:
0.0000496
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000641
Gnomad4 OTH exome
AF:
0.0000341
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152180
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74396
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000518
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.00000867
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Nov 27, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.230C>T (p.A77V) alteration is located in exon 1 (coding exon 1) of the DRD4 gene. This alteration results from a C to T substitution at nucleotide position 230, causing the alanine (A) at amino acid position 77 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Pathogenic
26
DANN
Uncertain
1.0
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Pathogenic
0.97
D
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Benign
-0.46
T
PrimateAI
Pathogenic
0.90
D
PROVEAN
Uncertain
-3.4
D
REVEL
Uncertain
0.38
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Vest4
0.81
MVP
0.66
MPC
0.28
ClinPred
0.97
D
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.3
gMVP
0.83

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.

Other links and lift over

dbSNP: rs745308930; hg19: chr11-637534; API