dbSNP rs2229126: ADRA1A:p.Glu465Asp (chr8-26770155-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.029 ( 83 hom., cov: 32)

Exomes 𝑓: 0.029 ( 722 hom. )

Consequence

ADRA1A
NM_000680.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.110

Publications

10 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000680.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADRA1A	NM_000680.4	MANE Select	c.1395A>T	p.Glu465Asp	missense	Exon 3 of 3	NP_000671.2
ADRA1A	NM_033303.4		c.1269+126A>T		intron	N/A	NP_150646.3
ADRA1A	NM_033304.3		c.1269+126A>T		intron	N/A	NP_150647.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ADRA1A	ENST00000380573.4	TSL:2 MANE Select	c.1395A>T	p.Glu465Asp	missense	Exon 3 of 3	ENSP00000369947.3
ADRA1A	ENST00000276393.8	TSL:1	c.1395A>T	p.Glu465Asp	missense	Exon 2 of 2	ENSP00000276393.4
ADRA1A	ENST00000380586.5	TSL:1	c.1269+126A>T		intron	N/A	ENSP00000369960.1

Frequencies

GnomAD3 genomes

AF:

0.0294

AC:

4469

AN:

152126

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0362

AC:

7284

AN:

200972

AF XY:

0.0335

show subpopulations

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 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.:

AF XY:

0.0280

AC XY:

19199

AN XY:

685884

show subpopulations

African (AFR)

AF:

0.0250

AC:

788

AN:

31472

American (AMR)

AF:

0.0782

AC:

2860

AN:

36596

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

293

AN:

21616

East Asian (EAS)

AF:

0.0372

AC:

1454

AN:

39132

South Asian (SAS)

AF:

0.0159

AC:

1179

AN:

74090

European-Finnish (FIN)

AF:

0.0264

AC:

1335

AN:

50664

Middle Eastern (MID)

AF:

0.0231

AC:

125

AN:

5422

European-Non Finnish (NFE)

AF:

0.0281

AC:

30298

AN:

1078676

Other (OTH)

AF:

0.0308

AC:

1765

AN:

57384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

2166

4332

6498

8664

10830

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1218

2436

3654

4872

6090

<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:

0.0293

AC:

4468

AN:

152244

Hom.:

Cov.:

AF XY:

0.0304

AC XY:

2261

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0242

AC:

1004

AN:

41546

American (AMR)

AF:

0.0612

AC:

936

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3472

East Asian (EAS)

AF:

0.0445

AC:

230

AN:

5172

South Asian (SAS)

AF:

0.0135

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0291

AC:

309

AN:

10618

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0263

AC:

1791

AN:

68000

Other (OTH)

AF:

0.0261

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

230

460

690

920

1150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0228

Hom.:

Bravo

AF:

0.0328

TwinsUK

AF:

0.0262

AC:

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.033

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.14

PhyloP100

0.11

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.22

REVEL

Benign

0.23

Sift

Benign

0.49

Sift4G

Benign

0.56

Polyphen

0.0

Vest4

0.20

MutPred

0.026

Loss of disorder (P = 0.3186)

ClinPred

0.013

GERP RS

2.1

Varity_R

0.044

Mutation Taster

=95/5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over