3-114139600-T-C

Variant names:

• chr3-114139600-T-C
• NM_000796.6:c.623A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000796.6(DRD3):​c.623A>G​(p.Tyr208Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DRD3 NM_000796.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.70

Genes affected

DRD3 (HGNC:3024): (dopamine receptor D3) This gene encodes the D3 subtype of the five (D1-D5) dopamine receptors. The activity of the D3 subtype receptor is mediated by G proteins which inhibit adenylyl cyclase. This receptor is localized to the limbic areas of the brain, which are associated with cognitive, emotional, and endocrine functions. Genetic variation in this gene may be associated with susceptibility to hereditary essential tremor 1. Alternative splicing of this gene results in transcript variants encoding different isoforms, although some variants may be subject to nonsense-mediated decay (NMD). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRD3	NM_000796.6	c.623A>G	p.Tyr208Cys	missense_variant	Exon 5 of 7	ENST00000383673.5	NP_000787.2
DRD3	NM_001282563.2	c.623A>G	p.Tyr208Cys	missense_variant	Exon 6 of 8		NP_001269492.1
DRD3	NM_001290809.1	c.623A>G	p.Tyr208Cys	missense_variant	Exon 6 of 8		NP_001277738.1
DRD3	NM_033663.6	c.623A>G	p.Tyr208Cys	missense_variant	Exon 5 of 8		NP_387512.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRD3	ENST00000383673.5	c.623A>G	p.Tyr208Cys	missense_variant	Exon 5 of 7	1	NM_000796.6	ENSP00000373169.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.623A>G (p.Y208C) alteration is located in exon 5 (coding exon 4) of the DRD3 gene. This alteration results from a A to G substitution at nucleotide position 623, causing the tyrosine (Y) at amino acid position 208 to be replaced by a cysteine (C). 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	0.87
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;.;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.40	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.5	D;D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.95
MutPred		0.86		Loss of MoRF binding (P = 0.1133);Loss of MoRF binding (P = 0.1133);Loss of MoRF binding (P = 0.1133);Loss of MoRF binding (P = 0.1133);
MVP		0.96
MPC		1.3
ClinPred		1.0	D
GERP RS		5.1
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-113858447;