Genetic Variant ADRA1A:p.Gly247Arg (chr8-26864231-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000680.4(ADRA1A):c.739G>A(p.Gly247Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,614,198 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.0031 ( 11 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 53 hom. )

Consequence

ADRA1A
NM_000680.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.09

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034636557).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00309 (471/152344) while in subpopulation AMR AF = 0.0246 (376/15310). AF 95% confidence interval is 0.0225. There are 11 homozygotes in GnomAd4. There are 274 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRA1A	NM_000680.4 link	c.739G>A	p.Gly247Arg	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.739G>A	p.Gly247Arg	missense_variant	Exon 2 of 3	2	NM_000680.4	ENSP00000369947.3		P35348-1

Frequencies

GnomAD3 genomes

AF:

0.00309

AC:

471

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0246

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0114

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00670

AC:

1683

AN:

251314

AF XY:

0.00520

show subpopulations

Gnomad AFR exome

AF:

0.000678

Gnomad AMR exome

AF:

0.0416

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0115

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00180

AC:

2638

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

1159

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.0384

AC:

1718

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0204

AC:

808

AN:

39700

South Asian (SAS)

AF:

0.000209

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1112010

Other (OTH)

AF:

0.00119

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

165

330

496

661

826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00309

AC:

471

AN:

152344

Hom.:

Cov.:

AF XY:

0.00368

AC XY:

274

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41576

American (AMR)

AF:

0.0246

AC:

376

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0114

AC:

AN:

5182

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00102

Hom.:

Bravo

AF:

0.00451

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00496

AC:

602

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.020

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

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.93

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

MetaRNN

Benign

0.0035

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

MetaSVM

Benign

-0.52

MutationAssessor

Benign

0.20

N;N;.;N;N;N;N

PhyloP100

1.1

PrimateAI

Benign

0.41

PROVEAN

Benign

0.58

N;N;N;N;N;N;N

REVEL

Benign

0.18

Sift

Benign

0.19

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

Sift4G

Benign

0.42

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

Polyphen

0.0080, 0.15, 0.037

.;B;.;B;B;B;.

Vest4

0.082

MutPred

0.50

Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);Gain of MoRF binding (P = 0.0134);

MVP

0.92

MPC

0.36

ClinPred

0.012

GERP RS

3.4

Varity_R

0.049

gMVP

0.53

Mutation Taster

=99/1

polymorphism

(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