dbSNP rs2229125: ADRA1A:p.Ile200Ser (chr8-26864371-A-C) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -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.

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

Publications

16 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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, max_spliceai, 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 rank	MANE	Protein	UniProt
ADRA1A	NM_000680.4 link	c.599T>G	p.Ile200Ser	missense_variant	Exon 2 of 3	ENST00000380573.4	NP_000671.2	P35348-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADRA1A	ENST00000380573.4 link	c.599T>G	p.Ile200Ser	missense_variant	Exon 2 of 3	2	NM_000680.4	ENSP00000369947.3		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

GnomAD2 exomes

AF:

0.0260

AC:

6512

AN:

250510

AF XY:

0.0257

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 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

African (AFR)

AF:

0.00406

AC:

136

AN:

33480

American (AMR)

AF:

0.0593

AC:

2649

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00474

AC:

124

AN:

26134

East Asian (EAS)

AF:

0.00128

AC:

AN:

39700

South Asian (SAS)

AF:

0.0312

AC:

2688

AN:

86244

European-Finnish (FIN)

AF:

0.0217

AC:

1156

AN:

53224

Middle Eastern (MID)

AF:

0.0140

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0255

AC:

28347

AN:

1111980

Other (OTH)

AF:

0.0229

AC:

1383

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

2411

4822

7233

9644

12055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1120

2240

3360

4480

5600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0205

AC:

3125

AN:

152290

Hom.:

Cov.:

AF XY:

0.0215

AC XY:

1599

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00481

AC:

200

AN:

41570

American (AMR)

AF:

0.0468

AC:

716

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00519

AC:

AN:

3470

East Asian (EAS)

AF:

0.000774

AC:

AN:

5166

South Asian (SAS)

AF:

0.0328

AC:

158

AN:

4824

European-Finnish (FIN)

AF:

0.0214

AC:

227

AN:

10620

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0251

AC:

1709

AN:

68022

Other (OTH)

AF:

0.0203

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

160

320

479

639

799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0219

Hom.:

140

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

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

.;.;.;.;T;T;.

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

PhyloP100

9.3

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over