chr8-37966280-A-G

Variant names:

• chr8-37966280-A-G
• rs4994
• NM_000025.3:c.190T>C

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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
• Publications: 630 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRB3	NM_000025.3	MANE Select	c.190T>C	p.Trp64Arg	missense	Exon 1 of 2	NP_000016.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADRB3	ENST00000345060.5	TSL:1 MANE Select	c.190T>C	p.Trp64Arg	missense	Exon 1 of 2	ENSP00000343782.3
	ADRB3	ENST00000520341.2	TSL:6	n.318T>C		non_coding_transcript_exon	Exon 1 of 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

GnomAD2 exomes AF: 0.106 AC: 26242 AN: 247172 AF XY: 0.103

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 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

African (AFR) AF: 0.106 AC: 3562 AN: 33468

American (AMR) AF: 0.197 AC: 8816 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 1302 AN: 26108

East Asian (EAS) AF: 0.165 AC: 6535 AN: 39688

South Asian (SAS) AF: 0.128 AC: 11025 AN: 86242

European-Finnish (FIN) AF: 0.0826 AC: 4397 AN: 53252

Middle Eastern (MID) AF: 0.0711 AC: 410 AN: 5768

European-Non Finnish (NFE) AF: 0.0783 AC: 87085 AN: 1111764

Other (OTH) AF: 0.0895 AC: 5401 AN: 60362

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

African (AFR) AF: 0.105 AC: 4348 AN: 41558

American (AMR) AF: 0.138 AC: 2106 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3470

East Asian (EAS) AF: 0.145 AC: 747 AN: 5164

South Asian (SAS) AF: 0.130 AC: 628 AN: 4830

European-Finnish (FIN) AF: 0.0806 AC: 856 AN: 10620

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0745 AC: 5069 AN: 68004

Other (OTH) AF: 0.0843 AC: 178 AN: 2112

Alfa AF: 0.0808 Hom.: 1658

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	-	Obesity (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.1
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
PromoterAI		0.020	Neutral
Varity_R		0.11
gMVP		0.40
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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