10-111079524-T-G

Variant names:

• chr10-111079524-T-G
• rs34303217
• NM_000681.4:c.*130T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000681.4(ADRA2A):​c.*130T>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 0.0000012 in 835,968 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: ADRA2A NM_000681.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.38
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRA2A	NM_000681.4	MANE Select	c.*130T>G		3_prime_UTR	Exon 1 of 1	NP_000672.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRA2A	ENST00000280155.4	TSL:6 MANE Select	c.*130T>G		3_prime_UTR	Exon 1 of 1	ENSP00000280155.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000120 AC: 1 AN: 835968 Hom.: 0 Cov.: 11 AF XY: 0.00000236 AC XY: 1 AN XY: 423172

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19748

American (AMR) AF: 0.00 AC: 0 AN: 24708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16710

East Asian (EAS) AF: 0.0000291 AC: 1 AN: 34338

South Asian (SAS) AF: 0.00 AC: 0 AN: 57184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2702

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 595782

Other (OTH) AF: 0.00 AC: 0 AN: 38668

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.48
DANN	Benign	0.67
PhyloP100		-2.4

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: rs34303217; hg19: chr10-112839282;