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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000025.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRB3	NM_000025.3	MANE Select	c.800C>T	p.Ala267Val	missense	Exon 1 of 2	NP_000016.1	P13945

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADRB3	ENST00000345060.5	TSL:1 MANE Select	c.800C>T	p.Ala267Val	missense	Exon 1 of 2	ENSP00000343782.3	P13945
ENSG00000285880	ENST00000647937.1		c.284C>T	p.Ala95Val	missense	Exon 1 of 2	ENSP00000497740.1	A0A3B3IT50
ADRB3	ENST00000520341.2	TSL:6	n.928C>T		non_coding_transcript_exon	Exon 1 of 1

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

Age Distribution

Exome Het

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

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 v4.9

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

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.51

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.094

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.90

PhyloP100

4.9

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.73

REVEL

Benign

0.11

Sift

Benign

0.52

Sift4G

Benign

0.24

Polyphen

0.033

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over