3-114139503-C-T

Variant names:

• chr3-114139503-C-T
• rs2251177
• NM_000796.6:c.720G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000796.6(DRD3):​c.720G>A​(p.Gln240Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.992 in 1,613,062 control chromosomes in the GnomAD database, including 793,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70843 hom., cov: 31)
  • Exomes 𝑓: 0.99 (722948 hom.)
• Consequence: DRD3 NM_000796.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0870

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 3-114139503-C-T is Benign according to our data. Variant chr3-114139503-C-T is described in ClinVar as [Benign]. Clinvar id is 342598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.087 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRD3	NM_000796.6	c.720G>A	p.Gln240Gln	synonymous_variant	Exon 5 of 7	ENST00000383673.5	NP_000787.2
DRD3	NM_001282563.2	c.720G>A	p.Gln240Gln	synonymous_variant	Exon 6 of 8		NP_001269492.1
DRD3	NM_001290809.1	c.720G>A	p.Gln240Gln	synonymous_variant	Exon 6 of 8		NP_001277738.1
DRD3	NM_033663.6	c.720G>A	p.Gln240Gln	synonymous_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.720G>A	p.Gln240Gln	synonymous_variant	Exon 5 of 7	1	NM_000796.6	ENSP00000373169.2

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146525 AN: 152148 Hom.: 70807 Cov.: 31

Gnomad AFR AF: 0.875

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.987

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.971

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.974

GnomAD3 exomes AF: 0.987 AC: 247620 AN: 250788 Hom.: 122387 AF XY: 0.989 AC XY: 133982 AN XY: 135490

Gnomad AFR exome AF: 0.874

Gnomad AMR exome AF: 0.994

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.974

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.994

GnomAD4 exome AF: 0.995 AC: 1452984 AN: 1460796 Hom.: 722948 Cov.: 45 AF XY: 0.994 AC XY: 722631 AN XY: 726678

Gnomad4 AFR exome AF: 0.871

Gnomad4 AMR exome AF: 0.993

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.975

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.990

GnomAD4 genome AF: 0.963 AC: 146615 AN: 152266 Hom.: 70843 Cov.: 31 AF XY: 0.963 AC XY: 71715 AN XY: 74436

Gnomad4 AFR AF: 0.874

Gnomad4 AMR AF: 0.987

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.971

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.974

Alfa AF: 0.992 Hom.: 76982

Bravo AF: 0.959

Asia WGS AF: 0.982 AC: 3416 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tremor, hereditary essential, 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.1
DANN	Benign	0.55

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: rs2251177; hg19: chr3-113858350;