4-9783007-C-T

Variant names:

• chr4-9783007-C-T
• rs6283
• NM_000798.5:c.978C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.51
• Publications: 43 publications found

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]

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 Gene-Disease associations (from GenCC):

• hypouricemia, renal, 2

  Inheritance: AD, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary renal hypouricemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000798.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRD5	NM_000798.5	MANE Select	c.978C>T	p.Pro326Pro	synonymous	Exon 1 of 1	NP_000789.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRD5	ENST00000304374.4	TSL:6 MANE Select	c.978C>T	p.Pro326Pro	synonymous	Exon 1 of 1	ENSP00000306129.2
	DRD5	ENST00000888644.1		c.978C>T	p.Pro326Pro	synonymous	Exon 2 of 2	ENSP00000558703.1
	DRD5	ENST00000953045.1		c.978C>T	p.Pro326Pro	synonymous	Exon 2 of 2	ENSP00000623104.1

Frequencies

GnomAD3 genomes AF: 0.642 AC: 97542 AN: 151990 Hom.: 31553 Cov.: 33

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

GnomAD2 exomes AF: 0.644 AC: 161362 AN: 250654 AF XY: 0.644

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 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.: 85 AF XY: 0.652 AC XY: 474252 AN XY: 727228

African (AFR) AF: 0.601 AC: 20108 AN: 33480

American (AMR) AF: 0.649 AC: 29025 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 19322 AN: 26136

East Asian (EAS) AF: 0.613 AC: 24318 AN: 39700

South Asian (SAS) AF: 0.607 AC: 52332 AN: 86258

European-Finnish (FIN) AF: 0.601 AC: 32102 AN: 53408

Middle Eastern (MID) AF: 0.710 AC: 4096 AN: 5768

European-Non Finnish (NFE) AF: 0.659 AC: 733217 AN: 1111998

Other (OTH) AF: 0.655 AC: 39546 AN: 60396

GnomAD4 genome AF: 0.642 AC: 97611 AN: 152108 Hom.: 31580 Cov.: 33 AF XY: 0.637 AC XY: 47355 AN XY: 74358

African (AFR) AF: 0.610 AC: 25316 AN: 41498

American (AMR) AF: 0.670 AC: 10249 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 2589 AN: 3466

East Asian (EAS) AF: 0.613 AC: 3159 AN: 5152

South Asian (SAS) AF: 0.615 AC: 2967 AN: 4826

European-Finnish (FIN) AF: 0.589 AC: 6236 AN: 10580

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.660 AC: 44840 AN: 67984

Other (OTH) AF: 0.654 AC: 1380 AN: 2110

Alfa AF: 0.656 Hom.: 25131

Bravo AF: 0.647

Asia WGS AF: 0.611 AC: 2125 AN: 3478

EpiCase AF: 0.669

EpiControl AF: 0.677

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Schizophrenia;CN324066:Hereditary attention deficit-hyperactivity disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.8
DANN	Benign	0.89
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6283; hg19: chr4-9784631; COSMIC: COSV58576720;