Genetic Variant ADRA1A:c.-687+127G>A (chr8-26866809-C-T) – 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.-687+127G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 921,656 control chromosomes in the GnomAD database, including 40,430 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 0.28 ( 6257 hom., cov: 31)

Exomes 𝑓: 0.30 ( 34173 hom. )

Consequence

ADRA1A
NM_000680.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.413

Publications

14 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:

ENSG00000303788 (HGNC:):

ENSG00000303788 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 (BayesDel_noAF=-0.73).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRA1A	NM_000680.4 link	c.-687+127G>A		intron_variant	Intron 1 of 2	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.-687+127G>A		intron_variant	Intron 1 of 2	2	NM_000680.4	ENSP00000369947.3		P35348-1
ENSG00000303788	ENST00000797227.1 link	n.124+518C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.279

AC:

42434

AN:

151822

Hom.:

6251

Cov.:

show subpopulations

Gnomad AFR

AF:

0.209

Gnomad AMI

AF:

0.320

Gnomad AMR

AF:

0.307

Gnomad ASJ

AF:

0.290

Gnomad EAS

AF:

0.389

Gnomad SAS

AF:

0.520

Gnomad FIN

AF:

0.312

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.285

Gnomad OTH

AF:

0.278

GnomAD4 exome

AF:

0.295

AC:

227283

AN:

769716

Hom.:

34173

AF XY:

0.295

AC XY:

105186

AN XY:

356700

show subpopulations

African (AFR)

AF:

0.204

AC:

2998

AN:

14690

American (AMR)

AF:

0.331

AC:

301

AN:

910

Ashkenazi Jewish (ASJ)

AF:

0.291

AC:

1381

AN:

4750

East Asian (EAS)

AF:

0.385

AC:

1311

AN:

3402

South Asian (SAS)

AF:

0.500

AC:

7654

AN:

15308

European-Finnish (FIN)

AF:

0.301

AC:

AN:

322

Middle Eastern (MID)

AF:

0.323

AC:

492

AN:

1524

European-Non Finnish (NFE)

AF:

0.292

AC:

205379

AN:

703560

Other (OTH)

AF:

0.304

AC:

7670

AN:

25250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

7334

14667

22001

29334

36668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9416

18832

28248

37664

47080

<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:

0.279

AC:

42459

AN:

151940

Hom.:

6257

Cov.:

AF XY:

0.289

AC XY:

21480

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.209

AC:

8672

AN:

41458

American (AMR)

AF:

0.307

AC:

4689

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.290

AC:

1006

AN:

3470

East Asian (EAS)

AF:

0.389

AC:

1987

AN:

5108

South Asian (SAS)

AF:

0.520

AC:

2496

AN:

4798

European-Finnish (FIN)

AF:

0.312

AC:

3303

AN:

10578

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.285

AC:

19338

AN:

67938

Other (OTH)

AF:

0.275

AC:

582

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

1457

2913

4370

5826

7283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

468

936

1404

1872

2340

<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:

0.287

Hom.:

20271

Bravo

AF:

0.273

Asia WGS

AF:

0.421

AC:

1464

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.7

(source)

DANN

Benign

0.78

PhyloP100

-0.41

PromoterAI

0.012

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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