rs2229126

chr8-26770155-T-Achr8-26770155-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000680.4(ADRA1A):c.1395A>T(p.Glu465Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,547,296 control chromosomes in the GnomAD database, including 805 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.029 (83 hom., cov: 32)
  • Exomes 𝑓: 0.029 (722 hom.)
• Consequence: ADRA1A NM_000680.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.110

Genes affected

ADRA1A (HGNC:277): (adrenoceptor alpha 1A) Alpha-1-adrenergic receptors (alpha-1-ARs) are members of the G protein-coupled receptor superfamily. They activate mitogenic responses and regulate growth and proliferation of many cells. There are 3 alpha-1-AR subtypes: alpha-1A, -1B and -1D, all of which signal through the Gq/11 family of G-proteins and different subtypes show different patterns of activation. This gene encodes alpha-1A-adrenergic receptor. Alternative splicing of this gene generates four transcript variants, which encode four different isoforms with distinct C-termini but having similar ligand binding properties. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014440715).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADRA1A	NM_000680.4	c.1395A>T	p.Glu465Asp	missense_variant	3/3	ENST00000380573.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADRA1A	ENST00000380573.4	c.1395A>T	p.Glu465Asp	missense_variant	3/3	2	NM_000680.4	P1

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4469 AN: 152126 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.0242

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0611

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.0449

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0291

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0263

Gnomad OTH AF: 0.0259

GnomAD3 exomes AF: 0.0362 AC: 7284 AN: 200972 Hom.: 201 AF XY: 0.0335 AC XY: 3543 AN XY: 105836

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.0857

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.0520

Gnomad SAS exome AF: 0.0163

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.0279

Gnomad OTH exome AF: 0.0321

GnomAD4 exome AF: 0.0287 AC: 40097 AN: 1395052 Hom.: 722 Cov.: 33 AF XY: 0.0280 AC XY: 19199 AN XY: 685884

Gnomad4 AFR exome AF: 0.0250

Gnomad4 AMR exome AF: 0.0782

Gnomad4 ASJ exome AF: 0.0136

Gnomad4 EAS exome AF: 0.0372

Gnomad4 SAS exome AF: 0.0159

Gnomad4 FIN exome AF: 0.0264

Gnomad4 NFE exome AF: 0.0281

Gnomad4 OTH exome AF: 0.0308

GnomAD4 genome AF: 0.0293 AC: 4468 AN: 152244 Hom.: 83 Cov.: 32 AF XY: 0.0304 AC XY: 2261 AN XY: 74442

Gnomad4 AFR AF: 0.0242

Gnomad4 AMR AF: 0.0612

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.0445

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.0291

Gnomad4 NFE AF: 0.0263

Gnomad4 OTH AF: 0.0261

Alfa AF: 0.0228 Hom.: 38

Bravo AF: 0.0328

TwinsUK AF: 0.0262 AC: 97

ALSPAC AF: 0.0267 AC: 103

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.0244 AC: 210

ExAC AF: 0.0314 AC: 3792

Asia WGS AF: 0.0350 AC: 120 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.033	T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.67	D
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.14	N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.22	N;N
REVEL	Benign	0.23
Sift	Benign	0.49	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0	B;B
Vest4		0.20
MutPred		0.026		Loss of disorder (P = 0.3186);Loss of disorder (P = 0.3186);
ClinPred		0.013	T
GERP RS		2.1
Varity_R		0.044

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: rs2229126; hg19: chr8-26627672; COSMIC: COSV52376580; COSMIC: COSV52376580;