Genetic Variant ADRB3:p.Arg362Leu (chr8-37965385-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000025.3(ADRB3):c.1085G>T(p.Arg362Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000711 in 1,546,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R362P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000036 ( 0 hom. )

Consequence

ADRB3
NM_000025.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.24

Publications

0 publications found

Variant links:

Genes affected

ADRB3 (HGNC:288): (adrenoceptor beta 3) The protein encoded by this gene belongs to the family of beta adrenergic receptors, which mediate catecholamine-induced activation of adenylate cyclase through the action of G proteins. This receptor is located mainly in the adipose tissue and is involved in the regulation of lipolysis and thermogenesis. Obesity and bodyweight-related disorders are correlated with certain polymorphisms in three subtypes of beta-adrenoceptor, among them, the ADRB3 gene.[provided by RefSeq, Oct 2019]

ADRB3 links:

ENSG00000285880 (HGNC:):

ENSG00000285880 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09607017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRB3	NM_000025.3 link	c.1085G>T	p.Arg362Leu	missense_variant	Exon 1 of 2	ENST00000345060.5	NP_000016.1	P13945A8KAG8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADRB3	ENST00000345060.5 link	c.1085G>T	p.Arg362Leu	missense_variant	Exon 1 of 2	1	NM_000025.3	ENSP00000343782.3	P13945
ENSG00000285880	ENST00000647937.1 link	c.569G>T	p.Arg190Leu	missense_variant	Exon 1 of 2			ENSP00000497740.1	A0A3B3IT50
ADRB3	ENST00000520341.2 link	n.1213G>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000139

AC:

AN:

144264

AF XY:

0.0000129

show subpopulations

Gnomad AFR exome

AF:

0.000281

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000358

AC:

AN:

1394970

Hom.:

Cov.:

AF XY:

0.00000436

AC XY:

AN XY:

687992

show subpopulations

African (AFR)

AF:

0.0000961

AC:

AN:

31228

American (AMR)

AF:

0.00

AC:

AN:

35320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25074

East Asian (EAS)

AF:

0.00

AC:

AN:

35514

South Asian (SAS)

AF:

0.00

AC:

AN:

78694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47952

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5522

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1077846

Other (OTH)

AF:

0.00

AC:

AN:

57820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41378

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000416

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.052

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.0054

MetaRNN

Benign

0.096

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.2

.;M

PhyloP100

3.2

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.070

.;N

REVEL

Benign

0.084

Sift

Benign

0.23

.;T

Sift4G

Benign

0.19

.;T

Polyphen

0.014

.;B

Vest4

0.14

MutPred

0.46

.;Loss of MoRF binding (P = 0.0099);

MVP

0.43

MPC

1.2

ClinPred

0.045

GERP RS

1.8

Varity_R

0.059

gMVP

0.39

Mutation Taster

=78/22

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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chr8-37965385-C-A

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