rs3750625

Positions:

• chr10-111079843-C-A
• chr10-111079843-C-G
• chr10-111079843-C-T

Variant summary

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

The NM_000681.4(ADRA2A):​c.*449C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0807 in 182,962 control chromosomes in the GnomAD database, including 967 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.088 (883 hom., cov: 33)
  • Exomes 𝑓: 0.045 (84 hom.)
• Consequence: ADRA2A NM_000681.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.639

Genes affected

ADRA2A (HGNC:281): (adrenoceptor alpha 2A) Alpha-2-adrenergic receptors are members of the G protein-coupled receptor superfamily. The alpha-2-adrenergic receptors are a type of adrenergic receptors (for adrenaline or epinephrine), which inhibit adenylate cyclase. These receptors include 3 highly homologous subtypes: alpha2A, alpha2B, and alpha2C. They are involved in regulating the release of neurotransmitter molecules from sympathetic nerves and from adrenergic neurons in the central nervous system. The sympathetic nervous system regulates cardiovascular function by activating adrenergic receptors in the heart, blood vessels and kidney. Studies in mouse revealed that both the alpha2A and alpha2C receptor subtypes were required for presynaptic transmitter release from the sympathetic nervous system in the heart and from central noradrenergic neurons. The alpha-2-adrenergic receptors are also involved in catecholamine signaling by extracellular regulated protein kinase 1 and 2 (ERK1/2) pathways. A clear association between the alpha-2-adrenergic receptor and disease has not been yet established. [provided by RefSeq, Sep 2019]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADRA2A	NM_000681.4	c.*449C>A		3_prime_UTR_variant	1/1	ENST00000280155.4	NP_000672.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADRA2A	ENST00000280155.4	c.*449C>A		3_prime_UTR_variant	1/1		NM_000681.4	ENSP00000280155	P1

Frequencies

GnomAD3 genomes AF: 0.0880 AC: 13389 AN: 152146 Hom.: 883 Cov.: 33

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0644

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.190

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0460

Gnomad OTH AF: 0.0784

GnomAD4 exome AF: 0.0451 AC: 1386 AN: 30698 Hom.: 84 Cov.: 0 AF XY: 0.0477 AC XY: 719 AN XY: 15086

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.0604

Gnomad4 ASJ exome AF: 0.0578

Gnomad4 EAS exome AF: 0.220

Gnomad4 SAS exome AF: 0.219

Gnomad4 FIN exome AF: 0.0140

Gnomad4 NFE exome AF: 0.0488

Gnomad4 OTH exome AF: 0.0669

GnomAD4 genome AF: 0.0879 AC: 13384 AN: 152264 Hom.: 883 Cov.: 33 AF XY: 0.0873 AC XY: 6500 AN XY: 74446

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0643

Gnomad4 ASJ AF: 0.0487

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.161

Gnomad4 FIN AF: 0.0117

Gnomad4 NFE AF: 0.0460

Gnomad4 OTH AF: 0.0781

Alfa AF: 0.0500 Hom.: 126

Bravo AF: 0.0937

Asia WGS AF: 0.171 AC: 595 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.6
DANN	Benign	0.66

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: rs3750625; hg19: chr10-112839601;