Genetic Variant ADRB3:p.Ala267Val (chr8-37965670-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000025.3(ADRB3):c.800C>T(p.Ala267Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,386,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. A267D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ADRB3
NM_000025.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.93

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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.094145775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRB3	NM_000025.3 link	c.800C>T	p.Ala267Val	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.800C>T	p.Ala267Val	missense_variant	Exon 1 of 2	1	NM_000025.3	ENSP00000343782.3	P13945
ENSG00000285880	ENST00000647937.1 link	c.284C>T	p.Ala95Val	missense_variant	Exon 1 of 2			ENSP00000497740.1	A0A3B3IT50
ADRB3	ENST00000520341.2 link	n.928C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000152

AC:

AN:

131616

AF XY:

0.0000140

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000137

AC:

AN:

1386088

Hom.:

Cov.:

AF XY:

0.0000205

AC XY:

AN XY:

682910

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30452

American (AMR)

AF:

0.00

AC:

AN:

34286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24546

East Asian (EAS)

AF:

0.00

AC:

AN:

35072

South Asian (SAS)

AF:

0.000243

AC:

AN:

78180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5102

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074048

Other (OTH)

AF:

0.00

AC:

AN:

57378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000263

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.070

.;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.51

T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.094

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.90

.;L

PhyloP100

4.9

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.73

.;N

REVEL

Benign

0.11

Sift

Benign

0.52

.;T

Sift4G

Benign

0.24

.;T

Polyphen

0.033

.;B

Vest4

0.19

MutPred

0.34

.;Gain of catalytic residue at A267 (P = 0.0173);

MVP

0.81

MPC

1.4

ClinPred

0.12

GERP RS

3.8

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.084

gMVP

0.31

Mutation Taster

=97/3

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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chr8-37965670-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over