4-9782291-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000798.5(DRD5):c.262C>T(p.Leu88Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00727 in 1,614,012 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L88R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (12 hom., cov: 34)
  • Exomes 𝑓: 0.0075 (55 hom.)
• Consequence: DRD5 NM_000798.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.47

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020658612).
• BP6: Variant 4-9782291-C-T is Benign according to our data. Variant chr4-9782291-C-T is described in ClinVar as [Benign]. Clinvar id is 592325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-9782291-C-T is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 766 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DRD5	NM_000798.5	c.262C>T	p.Leu88Phe	missense_variant	1/1	ENST00000304374.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DRD5	ENST00000304374.4	c.262C>T	p.Leu88Phe	missense_variant	1/1		NM_000798.5	P1
SLC2A9	ENST00000503803.5	n.386-2226G>A		intron_variant, non_coding_transcript_variant		3
SLC2A9	ENST00000508585.5	n.182-10922G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00503 AC: 766 AN: 152274 Hom.: 12 Cov.: 34

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000658

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00780

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00466 AC: 1171 AN: 251058 Hom.: 2 AF XY: 0.00463 AC XY: 628 AN XY: 135704

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00734

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.000924

Gnomad NFE exome AF: 0.00714

Gnomad OTH exome AF: 0.00604

GnomAD4 exome AF: 0.00750 AC: 10961 AN: 1461620 Hom.: 55 Cov.: 31 AF XY: 0.00727 AC XY: 5287 AN XY: 727120

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00776

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.000986

Gnomad4 FIN exome AF: 0.000955

Gnomad4 NFE exome AF: 0.00904

Gnomad4 OTH exome AF: 0.00603

GnomAD4 genome AF: 0.00503 AC: 766 AN: 152392 Hom.: 12 Cov.: 34 AF XY: 0.00454 AC XY: 338 AN XY: 74528

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00712

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000658

Gnomad4 NFE AF: 0.00779

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00676 Hom.: 1

Bravo AF: 0.00536

TwinsUK AF: 0.0113 AC: 42

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00452 AC: 549

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00758

EpiControl AF: 0.00848

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 27, 2017

- -

DRD5-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2019

This variant is classified as 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	0.18
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.030	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.60
MPC		0.89
ClinPred		0.024	T
GERP RS		4.1
Varity_R		0.86
gMVP		0.73

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

Other links and lift over

dbSNP: rs148402761; hg19: chr4-9783915; COSMIC: COSV58577775;