Variant rs2229125 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3BP4_StrongBA1

The NM_000680.4(ADRA1A):c.599T>G(p.Ile200Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,613,918 control chromosomes in the GnomAD database, including 563 homozygotes. In-silico tool predicts 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 0.021 ( 50 hom., cov: 32)

Exomes 𝑓: 0.025 ( 513 hom. )

Consequence

ADRA1A
NM_000680.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.32

Variant links:

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]

ADRA1A links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN [when BayesDel_addAF, BayesDel_noAF, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.009888589).

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADRA1A	NM_000680.4 linkuse as main transcript	c.599T>G	p.Ile200Ser	missense_variant	2/3	ENST00000380573.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADRA1A	ENST00000380573.4 linkuse as main transcript	c.599T>G	p.Ile200Ser	missense_variant	2/3	2	NM_000680.4	P1	P35348-1

Frequencies

GnomAD3 genomes

AF:

0.0205

AC:

3127

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00483

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0468

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.000772

Gnomad SAS

AF:

0.0327

Gnomad FIN

AF:

0.0214

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0251

Gnomad OTH

AF:

0.0205

GnomAD3 exomes

AF:

0.0260

AC:

6512

AN:

250510

Hom.:

109

AF XY:

0.0257

AC XY:

3487

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.00402

Gnomad AMR exome

AF:

0.0616

Gnomad ASJ exome

AF:

0.00507

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0315

Gnomad FIN exome

AF:

0.0227

Gnomad NFE exome

AF:

0.0234

Gnomad OTH exome

AF:

0.0268

GnomAD4 exome

AF:

0.0251

AC:

36615

AN:

1461628

Hom.:

513

Cov.:

AF XY:

0.0250

AC XY:

18144

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00406

Gnomad4 AMR exome

AF:

0.0593

Gnomad4 ASJ exome

AF:

0.00474

Gnomad4 EAS exome

AF:

0.00128

Gnomad4 SAS exome

AF:

0.0312

Gnomad4 FIN exome

AF:

0.0217

Gnomad4 NFE exome

AF:

0.0255

Gnomad4 OTH exome

AF:

0.0229

GnomAD4 genome

AF:

0.0205

AC:

3125

AN:

152290

Hom.:

Cov.:

AF XY:

0.0215

AC XY:

1599

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00481

Gnomad4 AMR

AF:

0.0468

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.000774

Gnomad4 SAS

AF:

0.0328

Gnomad4 FIN

AF:

0.0214

Gnomad4 NFE

AF:

0.0251

Gnomad4 OTH

AF:

0.0203

Alfa

AF:

0.0211

Hom.:

Bravo

AF:

0.0221

TwinsUK

AF:

0.0229

AC:

ALSPAC

AF:

0.0353

AC:

136

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0245

AC:

211

ExAC

AF:

0.0243

AC:

2955

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.14

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D;D;D;.;D;D

MetaRNN

Benign

0.0099

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Pathogenic

3.6

H;H;.;H;H;H;H

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.9

D;D;D;D;D;D;D

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D

Polyphen

1.0

.;D;.;D;D;D;.

Vest4

0.72

MPC

1.2

ClinPred

0.054

GERP RS

5.1

Varity_R

0.97

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over