11-637495-C-T

Variant names:

• chr11-637495-C-T
• rs1367140126
• NM_000797.4:c.191C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000797.4(DRD4):​c.191C>T​(p.Ala64Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,400,380 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DRD4 NM_000797.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.93

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRD4	NM_000797.4	c.191C>T	p.Ala64Val	missense_variant	Exon 1 of 4	ENST00000176183.6	NP_000788.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRD4	ENST00000176183.6	c.191C>T	p.Ala64Val	missense_variant	Exon 1 of 4	1	NM_000797.4	ENSP00000176183.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1400380 Hom.: 0 Cov.: 32 AF XY: 0.00000289 AC XY: 2 AN XY: 692584

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.191C>T (p.A64V) 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 191, causing the alanine (A) at amino acid position 64 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	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.49	N
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.73	T
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Vest4		0.42
MutPred		0.47		Loss of disorder (P = 0.1158);
MVP		0.79
MPC		0.28
ClinPred		0.97	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
gMVP		0.47

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

Other links and lift over

dbSNP: rs1367140126; hg19: chr11-637495;