Genetic Variant ADRB3:p.Ala375Thr (chr8-37965347-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000025.3(ADRB3):c.1123G>A(p.Ala375Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,542,684 control chromosomes in the GnomAD database, including 2 homozygotes. 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. A375P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

ADRB3
NM_000025.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0310

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004799217).

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRB3	NM_000025.3 link	c.1123G>A	p.Ala375Thr	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.1123G>A	p.Ala375Thr	missense_variant	Exon 1 of 2	1	NM_000025.3	ENSP00000343782.3	P13945
ENSG00000285880	ENST00000647937.1 link	c.607G>A	p.Ala203Thr	missense_variant	Exon 1 of 2			ENSP00000497740.1	A0A3B3IT50
ADRB3	ENST00000520341.2 link	n.1251G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000800

AC:

109

AN:

136236

AF XY:

0.000849

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000358

Gnomad ASJ exome

AF:

0.0105

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000265

Gnomad OTH exome

AF:

0.00128

GnomAD4 exome

AF:

0.000247

AC:

343

AN:

1390380

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

180

AN XY:

685578

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30894

American (AMR)

AF:

0.000327

AC:

AN:

33688

Ashkenazi Jewish (ASJ)

AF:

0.00878

AC:

218

AN:

24822

East Asian (EAS)

AF:

0.00

AC:

AN:

35508

South Asian (SAS)

AF:

0.0000509

AC:

AN:

78554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47762

Middle Eastern (MID)

AF:

0.000815

AC:

AN:

4910

European-Non Finnish (NFE)

AF:

0.0000557

AC:

AN:

1076730

Other (OTH)

AF:

0.000800

AC:

AN:

57512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000263

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41584

American (AMR)

AF:

0.000131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68010

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00145

Hom.:

Bravo

AF:

0.000351

ExAC

AF:

0.000387

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.050

.;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.35

T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.0048

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;L

PhyloP100

-0.031

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.13

.;N

REVEL

Benign

0.038

Sift

Benign

0.17

.;T

Sift4G

Benign

0.17

.;T

Polyphen

0.0

.;B

Vest4

0.070

MVP

0.65

MPC

0.81

ClinPred

0.024

GERP RS

1.1

Varity_R

0.035

gMVP

0.29

Mutation Taster

=98/2

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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8-37965347-C-T

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