8-37965457-T-C

Position:

chr8-37965457-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000345060.5(ADRB3):c.1013A>G(p.Asn338Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,551,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

ADRB3
ENST00000345060.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 7.94

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18465862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADRB3	NM_000025.3 linkuse as main transcript	c.1013A>G	p.Asn338Ser	missense_variant	1/2	ENST00000345060.5	NP_000016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADRB3	ENST00000345060.5 linkuse as main transcript	c.1013A>G	p.Asn338Ser	missense_variant	1/2	1	NM_000025.3	ENSP00000343782	P1
ADRB3	ENST00000520341.2 linkuse as main transcript	n.1141A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00231

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000242

AC:

AN:

152744

Hom.:

AF XY:

0.000222

AC XY:

AN XY:

81226

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00225

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000210

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.000187

AC:

262

AN:

1399272

Hom.:

Cov.:

AF XY:

0.000177

AC XY:

122

AN XY:

690270

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000280

Gnomad4 ASJ exome

AF:

0.00250

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000252

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000150

Gnomad4 OTH exome

AF:

0.000379

GnomAD4 genome

AF:

0.000138

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00231

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000362

Hom.:

Bravo

AF:

0.000230

ExAC

AF:

0.0000615

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ADRB3 p.Asn338Ser variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs200277866) and in control databases in 39 of 184090 chromosomes at a frequency of 0.000212 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 20 of 8718 chromosomes (freq: 0.002294), Latino in 5 of 25570 chromosomes (freq: 0.000196), Other in 1 of 5446 chromosomes (freq: 0.000184) and European (non-Finnish) in 13 of 72636 chromosomes (freq: 0.000179); it was not observed in the African, East Asian, European (Finnish) and South Asian populations. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Asn338 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2022

The c.1013A>G (p.N338S) alteration is located in exon 1 (coding exon 1) of the ADRB3 gene. This alteration results from a A to G substitution at nucleotide position 1013, causing the asparagine (N) at amino acid position 338 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Obesity

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

.;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.18

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Uncertain

2.8

.;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.8

.;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

.;D

Vest4

0.81

MVP

0.89

MPC

1.7

ClinPred

0.39

GERP RS

3.5

Varity_R

0.89

gMVP

0.78

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over