rs4994

Positions:

• chr8-37966280-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000025.3(ADRB3):​c.190T>C​(p.Trp64Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0884 in 1,613,570 control chromosomes in the GnomAD database, including 7,132 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (769 hom., cov: 33)
  • Exomes 𝑓: 0.088 (6363 hom.)
• Consequence: ADRB3 NM_000025.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.05

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.1804395E-4).
• BP6: Variant 8-37966280-A-G is Benign according to our data. Variant chr8-37966280-A-G is described in ClinVar as [Benign]. Clinvar id is 17741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADRB3	NM_000025.3	c.190T>C	p.Trp64Arg	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	c.190T>C	p.Trp64Arg	missense_variant	1/2	1	NM_000025.3	ENSP00000343782	P1
ADRB3	ENST00000520341.2	n.318T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.0927 AC: 14099 AN: 152152 Hom.: 761 Cov.: 33

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0806

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0745

Gnomad OTH AF: 0.0847

GnomAD3 exomes AF: 0.106 AC: 26242 AN: 247172 Hom.: 1769 AF XY: 0.103 AC XY: 13824 AN XY: 134230

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.0482

Gnomad EAS exome AF: 0.142

Gnomad SAS exome AF: 0.128

Gnomad FIN exome AF: 0.0791

Gnomad NFE exome AF: 0.0742

Gnomad OTH exome AF: 0.0967

GnomAD4 exome AF: 0.0880 AC: 128533 AN: 1461300 Hom.: 6363 Cov.: 32 AF XY: 0.0882 AC XY: 64153 AN XY: 726968

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.197

Gnomad4 ASJ exome AF: 0.0499

Gnomad4 EAS exome AF: 0.165

Gnomad4 SAS exome AF: 0.128

Gnomad4 FIN exome AF: 0.0826

Gnomad4 NFE exome AF: 0.0783

Gnomad4 OTH exome AF: 0.0895

GnomAD4 genome AF: 0.0929 AC: 14139 AN: 152270 Hom.: 769 Cov.: 33 AF XY: 0.0952 AC XY: 7087 AN XY: 74464

Gnomad4 AFR AF: 0.105

Gnomad4 AMR AF: 0.138

Gnomad4 ASJ AF: 0.0487

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.0806

Gnomad4 NFE AF: 0.0745

Gnomad4 OTH AF: 0.0843

Alfa AF: 0.0759 Hom.: 930

Bravo AF: 0.0992

TwinsUK AF: 0.0720 AC: 267

ALSPAC AF: 0.0758 AC: 292

ESP6500AA AF: 0.106 AC: 468

ESP6500EA AF: 0.0756 AC: 649

ExAC AF: 0.102 AC: 12436

Asia WGS AF: 0.144 AC: 506 AN: 3478

EpiCase AF: 0.0700

EpiControl AF: 0.0707

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	This variant is associated with the following publications: (PMID: 9080262, 29670643, 22774474, 11380082, 21529759, 23729572, 21289629, 21358132, 20008926, 20069060, 11564599, 17225053, 19553224, 22550477, 19133996, 21285172, 21034552, 19080138, 7487991, 28456594, 23968135, 20078877, 23032405) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Obesity Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Oct 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.44
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.00082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.9	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	6.1	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.019
MutPred		0.23		Gain of methylation at W64 (P = 0.0847);
MPC		1.4
ClinPred		0.0028	T
GERP RS		2.4
Varity_R		0.11
gMVP		0.40

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

Other links and lift over

dbSNP: rs4994; hg19: chr8-37823798; COSMIC: COSV61461710;