3-114131137-T-C

Position:

• chr3-114131137-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000796.6(DRD3):​c.987A>G​(p.Gln329=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,613,948 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (47 hom.)
• Consequence: DRD3 NM_000796.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.15

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 3-114131137-T-C is Benign according to our data. Variant chr3-114131137-T-C is described in ClinVar as [Benign]. Clinvar id is 342596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1996/152314) while in subpopulation AFR AF= 0.0429 (1781/41562). AF 95% confidence interval is 0.0412. There are 36 homozygotes in gnomad4. There are 980 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DRD3	NM_000796.6	c.987A>G	p.Gln329=	synonymous_variant	6/7	ENST00000383673.5
DRD3	NM_001282563.2	c.987A>G	p.Gln329=	synonymous_variant	7/8
DRD3	NM_001290809.1	c.987A>G	p.Gln329=	synonymous_variant	7/8
DRD3	NM_033663.6	c.888A>G	p.Gln296=	synonymous_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DRD3	ENST00000383673.5	c.987A>G	p.Gln329=	synonymous_variant	6/7	1	NM_000796.6	P1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1983 AN: 152196 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0427

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00527 AC: 1324 AN: 251392 Hom.: 15 AF XY: 0.00469 AC XY: 637 AN XY: 135872

Gnomad AFR exome AF: 0.0444

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0122

Gnomad SAS exome AF: 0.00921

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00229 AC: 3352 AN: 1461634 Hom.: 47 Cov.: 31 AF XY: 0.00236 AC XY: 1714 AN XY: 727068

Gnomad4 AFR exome AF: 0.0470

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0138

Gnomad4 SAS exome AF: 0.00842

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000738

Gnomad4 OTH exome AF: 0.00477

GnomAD4 genome AF: 0.0131 AC: 1996 AN: 152314 Hom.: 36 Cov.: 32 AF XY: 0.0132 AC XY: 980 AN XY: 74484

Gnomad4 AFR AF: 0.0429

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0108

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00534 Hom.: 7

Bravo AF: 0.0146

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tremor, hereditary essential, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	7.3
DANN	Benign	0.62

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: rs61735073; hg19: chr3-113849984;