rs1800545

Variant names:

• chr10-111077780-G-A
• rs1800545
• NM_000681.4:c.-217G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000681.4(ADRA2A):​c.-217G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 498,550 control chromosomes in the GnomAD database, including 6,208 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 0.16 (2274 hom., cov: 32)
  • Exomes 𝑓: 0.14 (3934 hom.)
• Consequence: ADRA2A NM_000681.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.830
• Publications: 26 publications found

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]

ADRA2A Gene-Disease associations (from GenCC):

• lipodystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• lipodystrophy, familial partial, type 8

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000681.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRA2A	NM_000681.4	MANE Select	c.-217G>A		5_prime_UTR	Exon 1 of 1	NP_000672.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRA2A	ENST00000280155.4	TSL:6 MANE Select	c.-217G>A		5_prime_UTR	Exon 1 of 1	ENSP00000280155.2	P08913

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23565 AN: 151376 Hom.: 2274 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.0562

Gnomad AMR AF: 0.0911

Gnomad ASJ AF: 0.0594

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0863

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.136

GnomAD4 exome AF: 0.142 AC: 49432 AN: 347066 Hom.: 3934 Cov.: 6 AF XY: 0.141 AC XY: 24228 AN XY: 172422

African (AFR) AF: 0.320 AC: 2910 AN: 9094

American (AMR) AF: 0.0834 AC: 543 AN: 6512

Ashkenazi Jewish (ASJ) AF: 0.0730 AC: 644 AN: 8822

East Asian (EAS) AF: 0.267 AC: 5684 AN: 21276

South Asian (SAS) AF: 0.216 AC: 1206 AN: 5580

European-Finnish (FIN) AF: 0.0919 AC: 1734 AN: 18866

Middle Eastern (MID) AF: 0.154 AC: 222 AN: 1438

European-Non Finnish (NFE) AF: 0.131 AC: 33710 AN: 256626

Other (OTH) AF: 0.147 AC: 2779 AN: 18852

GnomAD4 genome AF: 0.156 AC: 23577 AN: 151484 Hom.: 2274 Cov.: 32 AF XY: 0.153 AC XY: 11350 AN XY: 74050

African (AFR) AF: 0.288 AC: 11860 AN: 41136

American (AMR) AF: 0.0910 AC: 1390 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0594 AC: 206 AN: 3470

East Asian (EAS) AF: 0.177 AC: 891 AN: 5042

South Asian (SAS) AF: 0.155 AC: 743 AN: 4786

European-Finnish (FIN) AF: 0.0863 AC: 914 AN: 10596

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7204 AN: 67872

Other (OTH) AF: 0.135 AC: 285 AN: 2104

Alfa AF: 0.133 Hom.: 3078

Bravo AF: 0.162

Asia WGS AF: 0.180 AC: 626 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Benign	0.94
PhyloP100		0.83
Mutation Taster		=296/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800545; hg19: chr10-112837538;