chr11-637294-C-T

Variant names:

• chr11-637294-C-T
• rs146680769
• NM_000797.4:c.-11C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000797.4(DRD4):​c.-11C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0517 in 1,196,094 control chromosomes in the GnomAD database, including 1,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.042 (157 hom., cov: 32)
  • Exomes 𝑓: 0.053 (1600 hom.)
• Consequence: DRD4 NM_000797.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0620

Genes affected

DRD4 (HGNC:3025): (dopamine receptor D4) This gene encodes the D4 subtype of the dopamine receptor. The D4 subtype is a G-protein coupled receptor which inhibits adenylyl cyclase. It is a target for drugs which treat schizophrenia and Parkinson disease. Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder, and the personality trait of novelty seeking. This gene contains a polymorphic number (2-10 copies) of tandem 48 nt repeats; the sequence shown contains four repeats. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0659 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRD4	NM_000797.4	c.-11C>T		5_prime_UTR_variant	Exon 1 of 4	ENST00000176183.6	NP_000788.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRD4	ENST00000176183	c.-11C>T		5_prime_UTR_variant	Exon 1 of 4	1	NM_000797.4	ENSP00000176183.5

Frequencies

GnomAD3 genomes AF: 0.0424 AC: 6396 AN: 150986 Hom.: 158 Cov.: 32

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.0905

Gnomad AMR AF: 0.0450

Gnomad ASJ AF: 0.0784

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.0712

Gnomad FIN AF: 0.0362

Gnomad MID AF: 0.0290

Gnomad NFE AF: 0.0536

Gnomad OTH AF: 0.0524

GnomAD3 exomes AF: 0.0515 AC: 319 AN: 6198 Hom.: 15 AF XY: 0.0503 AC XY: 201 AN XY: 3994

Gnomad AFR exome AF: 0.0263

Gnomad AMR exome AF: 0.0210

Gnomad ASJ exome AF: 0.0811

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0608

Gnomad FIN exome AF: 0.0332

Gnomad NFE exome AF: 0.0520

Gnomad OTH exome AF: 0.0333

GnomAD4 exome AF: 0.0530 AC: 55428 AN: 1045000 Hom.: 1600 Cov.: 30 AF XY: 0.0533 AC XY: 26405 AN XY: 495470

Gnomad4 AFR exome AF: 0.0186

Gnomad4 AMR exome AF: 0.0468

Gnomad4 ASJ exome AF: 0.0794

Gnomad4 EAS exome AF: 0.000190

Gnomad4 SAS exome AF: 0.0801

Gnomad4 FIN exome AF: 0.0379

Gnomad4 NFE exome AF: 0.0542

Gnomad4 OTH exome AF: 0.0574

GnomAD4 genome AF: 0.0424 AC: 6404 AN: 151094 Hom.: 157 Cov.: 32 AF XY: 0.0426 AC XY: 3146 AN XY: 73860

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.0450

Gnomad4 ASJ AF: 0.0784

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.0721

Gnomad4 FIN AF: 0.0362

Gnomad4 NFE AF: 0.0537

Gnomad4 OTH AF: 0.0523

Alfa AF: 0.0201 Hom.: 9

Bravo AF: 0.0428

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Potent mutations in Dopamine receptor uptake gene leads to decreased brain uptake of neuromodulator dopamine and are strongly associated with onset of Attention deficit hyperactivity disorder. However more evidence is required to confer the association of this particular rs146680769 with Attention deficit hyperactivity disorder. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.3
DANN	Benign	0.97

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: rs146680769; hg19: chr11-637294;