rs553668

Positions:

• chr10-111079821-A-G
• chr10-111079821-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The NM_000681.4(ADRA2A):​c.*427A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.783 in 187,948 control chromosomes in the GnomAD database, including 58,407 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.77 (46325 hom., cov: 34)
  • Exomes 𝑓: 0.82 (12082 hom.)
• Consequence: ADRA2A NM_000681.4 3_prime_UTR
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.429

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 -8 ACMG points.

• PP5: Variant 10-111079821-A-G is Pathogenic according to our data. Variant chr10-111079821-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2691730.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85). . Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.838 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADRA2A	NM_000681.4	c.*427A>G		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.*427A>G		3_prime_UTR_variant	1/1		NM_000681.4	ENSP00000280155	P1

Frequencies

GnomAD3 genomes AF: 0.775 AC: 117875 AN: 152106 Hom.: 46327 Cov.: 34

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.837

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.782

Gnomad EAS AF: 0.525

Gnomad SAS AF: 0.637

Gnomad FIN AF: 0.851

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.764

GnomAD4 exome AF: 0.818 AC: 29205 AN: 35724 Hom.: 12082 Cov.: 0 AF XY: 0.815 AC XY: 14422 AN XY: 17690

Gnomad4 AFR exome AF: 0.715

Gnomad4 AMR exome AF: 0.713

Gnomad4 ASJ exome AF: 0.808

Gnomad4 EAS exome AF: 0.529

Gnomad4 SAS exome AF: 0.678

Gnomad4 FIN exome AF: 0.841

Gnomad4 NFE exome AF: 0.850

Gnomad4 OTH exome AF: 0.798

GnomAD4 genome AF: 0.775 AC: 117911 AN: 152224 Hom.: 46325 Cov.: 34 AF XY: 0.768 AC XY: 57150 AN XY: 74436

Gnomad4 AFR AF: 0.706

Gnomad4 AMR AF: 0.726

Gnomad4 ASJ AF: 0.782

Gnomad4 EAS AF: 0.527

Gnomad4 SAS AF: 0.637

Gnomad4 FIN AF: 0.851

Gnomad4 NFE AF: 0.844

Gnomad4 OTH AF: 0.755

Alfa AF: 0.823 Hom.: 69565

Bravo AF: 0.763

Asia WGS AF: 0.558 AC: 1942 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lipodystrophy, familial partial, type 8 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.57

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: rs553668; hg19: chr10-112839579; COSMIC: COSV54528180;