rs11195419

Variant names:

• chr10-111079610-C-A
• rs11195419
• NM_000681.4:c.*216C>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.*216C>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 0.138 in 619,010 control chromosomes in the GnomAD database, including 7,071 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 (2442 hom., cov: 33)
  • Exomes 𝑓: 0.13 (4629 hom.)
• Consequence: ADRA2A NM_000681.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.357
• Publications: 34 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.275 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRA2A	NM_000681.4	c.*216C>A		3_prime_UTR_variant	Exon 1 of 1	ENST00000280155.4	NP_000672.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADRA2A	ENST00000280155.4	c.*216C>A		3_prime_UTR_variant	Exon 1 of 1	6	NM_000681.4	ENSP00000280155.2

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24390 AN: 152108 Hom.: 2442 Cov.: 33

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.0725

Gnomad AMR AF: 0.0993

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.177

Gnomad FIN AF: 0.0931

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.142

GnomAD4 exome AF: 0.131 AC: 61147 AN: 466784 Hom.: 4629 Cov.: 4 AF XY: 0.133 AC XY: 32464 AN XY: 244716

African (AFR) AF: 0.281 AC: 3507 AN: 12480

American (AMR) AF: 0.0779 AC: 1446 AN: 18566

Ashkenazi Jewish (ASJ) AF: 0.0754 AC: 1030 AN: 13654

East Asian (EAS) AF: 0.239 AC: 7424 AN: 31068

South Asian (SAS) AF: 0.184 AC: 8182 AN: 44436

European-Finnish (FIN) AF: 0.0943 AC: 4146 AN: 43956

Middle Eastern (MID) AF: 0.149 AC: 294 AN: 1976

European-Non Finnish (NFE) AF: 0.115 AC: 31570 AN: 274522

Other (OTH) AF: 0.136 AC: 3548 AN: 26126

GnomAD4 genome AF: 0.160 AC: 24395 AN: 152226 Hom.: 2442 Cov.: 33 AF XY: 0.158 AC XY: 11735 AN XY: 74440

African (AFR) AF: 0.279 AC: 11578 AN: 41524

American (AMR) AF: 0.0992 AC: 1518 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0686 AC: 238 AN: 3468

East Asian (EAS) AF: 0.192 AC: 995 AN: 5172

South Asian (SAS) AF: 0.176 AC: 848 AN: 4830

European-Finnish (FIN) AF: 0.0931 AC: 988 AN: 10612

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7822 AN: 68000

Other (OTH) AF: 0.142 AC: 299 AN: 2112

Alfa AF: 0.126 Hom.: 4498

Bravo AF: 0.164

Asia WGS AF: 0.186 AC: 648 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.8
DANN	Benign	0.79
PhyloP100		0.36
Mutation Taster		=100/0	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: rs11195419; hg19: chr10-112839368; COSMIC: COSV54527147;