Genetic Variant ADRB3:p.Leu317Met (chr8-37965521-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000025.3(ADRB3):c.949C>A(p.Leu317Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,360 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L317V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ADRB3
NM_000025.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.48

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRB3	NM_000025.3 link	c.949C>A	p.Leu317Met	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.949C>A	p.Leu317Met	missense_variant	Exon 1 of 2	1	NM_000025.3	ENSP00000343782.3	P13945
ENSG00000285880	ENST00000647937.1 link	c.433C>A	p.Leu145Met	missense_variant	Exon 1 of 2			ENSP00000497740.1	A0A3B3IT50
ADRB3	ENST00000520341.2 link	n.1077C>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000667

AC:

AN:

149862

AF XY:

0.0000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000879

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399360

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690254

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31668

American (AMR)

AF:

0.00

AC:

AN:

35764

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25166

East Asian (EAS)

AF:

0.0000279

AC:

AN:

35888

South Asian (SAS)

AF:

0.00

AC:

AN:

79278

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079284

Other (OTH)

AF:

0.00

AC:

AN:

58016

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.073

.;T

Eigen

Benign

0.14

Eigen_PC

Benign

0.067

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.031

MetaRNN

Uncertain

0.45

T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.6

.;L

PhyloP100

3.5

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.47

.;N

REVEL

Benign

0.17

Sift

Benign

0.075

.;T

Sift4G

Benign

0.21

.;T

Polyphen

0.84

.;P

Vest4

0.20

MutPred

0.65

.;Gain of catalytic residue at V313 (P = 0.0211);

MVP

0.59

MPC

1.9

ClinPred

0.39

GERP RS

2.8

PromoterAI

0.032

Neutral

(source)

Varity_R

0.094

gMVP

0.39

Mutation Taster

=70/30

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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8-37965521-G-T

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