4-9783510-T-C

Variant names:

• chr4-9783510-T-C
• rs1967551
• NM_000798.5:c.*47T>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000798.5(DRD5):​c.*47T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.608 in 1,525,428 control chromosomes in the GnomAD database, including 287,370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.55 (23725 hom., cov: 32)
  • Exomes 𝑓: 0.61 (263645 hom.)
• Consequence: DRD5 NM_000798.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.0160

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 4-9783510-T-C is Benign according to our data. Variant chr4-9783510-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1287057.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRD5	NM_000798.5	c.*47T>C		3_prime_UTR_variant	Exon 1 of 1	ENST00000304374.4	NP_000789.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRD5	ENST00000304374.4	c.*47T>C		3_prime_UTR_variant	Exon 1 of 1	6	NM_000798.5	ENSP00000306129.2
SLC2A9	ENST00000503803.5	n.386-3445A>G		intron_variant	Intron 3 of 3	3
SLC2A9	ENST00000508585.5	n.182-12141A>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.546 AC: 83023 AN: 151944 Hom.: 23712 Cov.: 32

Gnomad AFR AF: 0.397

Gnomad AMI AF: 0.555

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.641

Gnomad OTH AF: 0.545

GnomAD3 exomes AF: 0.564 AC: 107520 AN: 190510 Hom.: 31282 AF XY: 0.570 AC XY: 57865 AN XY: 101472

Gnomad AFR exome AF: 0.397

Gnomad AMR exome AF: 0.532

Gnomad ASJ exome AF: 0.695

Gnomad EAS exome AF: 0.338

Gnomad SAS exome AF: 0.458

Gnomad FIN exome AF: 0.607

Gnomad NFE exome AF: 0.646

Gnomad OTH exome AF: 0.586

GnomAD4 exome AF: 0.615 AC: 844278 AN: 1373366 Hom.: 263645 Cov.: 23 AF XY: 0.612 AC XY: 414116 AN XY: 676768

Gnomad4 AFR exome AF: 0.384

Gnomad4 AMR exome AF: 0.532

Gnomad4 ASJ exome AF: 0.685

Gnomad4 EAS exome AF: 0.364

Gnomad4 SAS exome AF: 0.467

Gnomad4 FIN exome AF: 0.615

Gnomad4 NFE exome AF: 0.644

Gnomad4 OTH exome AF: 0.587

GnomAD4 genome AF: 0.546 AC: 83058 AN: 152062 Hom.: 23725 Cov.: 32 AF XY: 0.543 AC XY: 40386 AN XY: 74330

Gnomad4 AFR AF: 0.396

Gnomad4 AMR AF: 0.552

Gnomad4 ASJ AF: 0.688

Gnomad4 EAS AF: 0.335

Gnomad4 SAS AF: 0.465

Gnomad4 FIN AF: 0.605

Gnomad4 NFE AF: 0.641

Gnomad4 OTH AF: 0.546

Alfa AF: 0.588 Hom.: 7939

Bravo AF: 0.537

Asia WGS AF: 0.393 AC: 1367 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary attention deficit-hyperactivity disorder Uncertain:1

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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A few studies show an association between dopamine(5) receptor uptake gene and ADHD. Howevr, more clinical studies are needed for a stronger correlation of this particular rs1967551 with Attention deficit hyperactivity disorder. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.2
DANN	Benign	0.29

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: rs1967551; hg19: chr4-9785134; COSMIC: COSV58577284;