10-111079821-A-G

Variant names:

• chr10-111079821-A-G
• rs553668
• NM_000681.4:c.*427A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 107 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 -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 VariationId 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.

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.*427A>G		3_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.*427A>G		3_prime_UTR	Exon 1 of 1	ENSP00000280155.2	P08913

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

African (AFR) AF: 0.715 AC: 608 AN: 850

American (AMR) AF: 0.713 AC: 1123 AN: 1574

Ashkenazi Jewish (ASJ) AF: 0.808 AC: 488 AN: 604

East Asian (EAS) AF: 0.529 AC: 696 AN: 1316

South Asian (SAS) AF: 0.678 AC: 633 AN: 934

European-Finnish (FIN) AF: 0.841 AC: 13030 AN: 15490

Middle Eastern (MID) AF: 0.720 AC: 59 AN: 82

European-Non Finnish (NFE) AF: 0.850 AC: 11489 AN: 13522

Other (OTH) AF: 0.798 AC: 1079 AN: 1352

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

African (AFR) AF: 0.706 AC: 29326 AN: 41536

American (AMR) AF: 0.726 AC: 11102 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 2712 AN: 3470

East Asian (EAS) AF: 0.527 AC: 2720 AN: 5166

South Asian (SAS) AF: 0.637 AC: 3075 AN: 4826

European-Finnish (FIN) AF: 0.851 AC: 9028 AN: 10606

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.844 AC: 57376 AN: 68012

Other (OTH) AF: 0.755 AC: 1594 AN: 2112

Alfa AF: 0.812 Hom.: 129852

Bravo AF: 0.763

Asia WGS AF: 0.558 AC: 1942 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Lipodystrophy, familial partial, type 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.4
DANN	Benign	0.57
PhyloP100		0.43
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: rs553668; hg19: chr10-112839579; COSMIC: COSV54528180;