10-111079134-C-T

Variant names:

• chr10-111079134-C-T
• rs1800038
• NM_000681.4:c.1138C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000681.4(ADRA2A):​c.1138C>T​(p.Arg380Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,392 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ADRA2A NM_000681.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.374
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1138C>T	p.Arg380Trp	missense	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.1138C>T	p.Arg380Trp	missense	Exon 1 of 1	ENSP00000280155.2	P08913

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450392 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720298

⚠️ 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: 33228

American (AMR) AF: 0.00 AC: 0 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25778

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.00 AC: 0 AN: 85638

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106044

Other (OTH) AF: 0.00 AC: 0 AN: 59956

⚠️ 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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.46	N
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.82	T
PhyloP100		0.37
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Vest4		0.34
MVP		0.36
ClinPred		0.83	D
GERP RS		2.6
gMVP		0.80
Mutation Taster		=67/33	polymorphism

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: rs1800038; hg19: chr10-112838892;