Genetic Variant DRD5:p.Pro326Pro (chr4-9783007-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_000798.5(DRD5):c.978C>T(p.Pro326Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,613,976 control chromosomes in the GnomAD database, including 343,664 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.64 ( 31580 hom., cov: 33)

Exomes 𝑓: 0.65 ( 312084 hom. )

Consequence

DRD5
NM_000798.5 synonymous

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.51

Variant links:

Genes affected

DRD5 (HGNC:3026): (dopamine receptor D5) This gene encodes the D5 subtype of the dopamine receptor. The D5 subtype is a G-protein coupled receptor which stimulates adenylyl cyclase. This receptor is expressed in neurons in the limbic regions of the brain. It has a 10-fold higher affinity for dopamine than the D1 subtype. Pseudogenes related to this gene reside on chromosomes 1 and 2. [provided by RefSeq, Jul 2008]

DRD5 links:

SLC2A9 (HGNC:13446): (solute carrier family 2 member 9) This gene encodes a member of the SLC2A facilitative glucose transporter family. Members of this family play a significant role in maintaining glucose homeostasis. The encoded protein may play a role in the development and survival of chondrocytes in cartilage matrices. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

SLC2A9 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP7

Synonymous conserved (PhyloP=-1.51 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRD5	NM_000798.5 link	c.978C>T	p.Pro326Pro	synonymous_variant	Exon 1 of 1	ENST00000304374.4	NP_000789.1	P21918

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DRD5	ENST00000304374.4 link	c.978C>T	p.Pro326Pro	synonymous_variant	Exon 1 of 1	6	NM_000798.5	ENSP00000306129.2	P21918
SLC2A9	ENST00000503803.5 link	n.386-2942G>A		intron_variant	Intron 3 of 3	3
SLC2A9	ENST00000508585.5 link	n.182-11638G>A		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.642

AC:

97542

AN:

151990

Hom.:

31553

Cov.:

show subpopulations

Gnomad AFR

AF:

0.610

Gnomad AMI

AF:

0.741

Gnomad AMR

AF:

0.670

Gnomad ASJ

AF:

0.747

Gnomad EAS

AF:

0.615

Gnomad SAS

AF:

0.614

Gnomad FIN

AF:

0.589

Gnomad MID

AF:

0.677

Gnomad NFE

AF:

0.660

Gnomad OTH

AF:

0.650

GnomAD3 exomes

AF:

0.644

AC:

161362

AN:

250654

Hom.:

51997

AF XY:

0.644

AC XY:

87354

AN XY:

135556

show subpopulations

Gnomad AFR exome

AF:

0.607

Gnomad AMR exome

AF:

0.645

Gnomad ASJ exome

AF:

0.743

Gnomad EAS exome

AF:

0.624

Gnomad SAS exome

AF:

0.603

Gnomad FIN exome

AF:

0.597

Gnomad NFE exome

AF:

0.663

Gnomad OTH exome

AF:

0.645

GnomAD4 exome

AF:

0.653

AC:

954066

AN:

1461868

Hom.:

312084

Cov.:

AF XY:

0.652

AC XY:

474252

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.601

Gnomad4 AMR exome

AF:

0.649

Gnomad4 ASJ exome

AF:

0.739

Gnomad4 EAS exome

AF:

0.613

Gnomad4 SAS exome

AF:

0.607

Gnomad4 FIN exome

AF:

0.601

Gnomad4 NFE exome

AF:

0.659

Gnomad4 OTH exome

AF:

0.655

GnomAD4 genome

AF:

0.642

AC:

97611

AN:

152108

Hom.:

31580

Cov.:

AF XY:

0.637

AC XY:

47355

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.610

Gnomad4 AMR

AF:

0.670

Gnomad4 ASJ

AF:

0.747

Gnomad4 EAS

AF:

0.613

Gnomad4 SAS

AF:

0.615

Gnomad4 FIN

AF:

0.589

Gnomad4 NFE

AF:

0.660

Gnomad4 OTH

AF:

0.654

Alfa

AF:

0.658

Hom.:

22779

Bravo

AF:

0.647

Asia WGS

AF:

0.611

AC:

2125

AN:

3478

EpiCase

AF:

0.669

EpiControl

AF:

0.677

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Schizophrenia;CN324066:Hereditary attention deficit-hyperactivity disorder

Uncertain:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Studies suggest an association between dopamine(5) receptor uptake gene and ADHD. Dysfunction of dopamine neurotransmission and its receptors can also lead to schizophrenia. However, more molecular evidence and clinical studies are needed for a stronger correlation of this particular variant rs6283 with Attention-deficit hyperactivity disorder and/or schizophrenia. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

1.8

DANN

Benign

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over