4-9782660-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000798.5(DRD5):c.631G>A(p.Asp211Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: DRD5 NM_000798.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.07

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056051016).
• BP6: Variant 4-9782660-G-A is Benign according to our data. Variant chr4-9782660-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3034554.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 250 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DRD5	NM_000798.5	c.631G>A	p.Asp211Asn	missense_variant	1/1	ENST00000304374.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DRD5	ENST00000304374.4	c.631G>A	p.Asp211Asn	missense_variant	1/1		NM_000798.5	P1
SLC2A9	ENST00000503803.5	n.386-2595C>T		intron_variant, non_coding_transcript_variant		3
SLC2A9	ENST00000508585.5	n.182-11291C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152224 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00574

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000462 AC: 116 AN: 250968 Hom.: 0 AF XY: 0.000332 AC XY: 45 AN XY: 135658

Gnomad AFR exome AF: 0.00604

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000168 AC: 245 AN: 1461662 Hom.: 0 Cov.: 31 AF XY: 0.000142 AC XY: 103 AN XY: 727140

Gnomad4 AFR exome AF: 0.00568

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152342 Hom.: 0 Cov.: 34 AF XY: 0.00142 AC XY: 106 AN XY: 74502

Gnomad4 AFR AF: 0.00572

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000704 Hom.: 1

Bravo AF: 0.00179

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000552 AC: 67

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DRD5-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 18, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	9.6
Dann	Benign	0.95
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.28	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.074
Sift	Benign	0.22	T
Sift4G	Benign	0.44	T
Polyphen		0.0030	B
Vest4		0.093
MVP		0.27
MPC		0.23
ClinPred		0.0046	T
GERP RS		2.8
Varity_R		0.063
gMVP		0.39

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: rs137945596; hg19: chr4-9784284;