8-37965413-G-A

Position:

• chr8-37965413-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000025.3(ADRB3):​c.1057C>T​(p.Arg353Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,549,182 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0083 (16 hom., cov: 33)
  • Exomes 𝑓: 0.00086 (12 hom.)
• Consequence: ADRB3 NM_000025.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.74

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]

ENSG00000285880 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005730182).
• BP6: Variant 8-37965413-G-A is Benign according to our data. Variant chr8-37965413-G-A is described in ClinVar as [Benign]. Clinvar id is 707946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00825 (1257/152276) while in subpopulation AFR AF= 0.0284 (1179/41548). AF 95% confidence interval is 0.027. There are 16 homozygotes in gnomad4. There are 612 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADRB3	NM_000025.3	c.1057C>T	p.Arg353Cys	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.1057C>T	p.Arg353Cys	missense_variant	1/2	1	NM_000025.3	ENSP00000343782.3
ENSG00000285880	ENST00000647937.1	c.541C>T	p.Arg181Cys	missense_variant	1/2			ENSP00000497740.1
ADRB3	ENST00000520341.2	n.1185C>T		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.00823 AC: 1252 AN: 152162 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00180 AC: 268 AN: 149062 Hom.: 2 AF XY: 0.00140 AC XY: 111 AN XY: 79542

Gnomad AFR exome AF: 0.0275

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000145

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.000862 AC: 1204 AN: 1396906 Hom.: 12 Cov.: 31 AF XY: 0.000740 AC XY: 510 AN XY: 689012

Gnomad4 AFR exome AF: 0.0299

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000177

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000705

Gnomad4 OTH exome AF: 0.00178

GnomAD4 genome AF: 0.00825 AC: 1257 AN: 152276 Hom.: 16 Cov.: 33 AF XY: 0.00822 AC XY: 612 AN XY: 74458

Gnomad4 AFR AF: 0.0284

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00126 Hom.: 7

Bravo AF: 0.00951

ESP6500AA AF: 0.0214 AC: 85

ESP6500EA AF: 0.000521 AC: 4

ExAC AF: 0.00156 AC: 131

Asia WGS AF: 0.00202 AC: 7 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.57	.;D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.6	.;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.1	.;D
REVEL	Benign	0.25
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	.;D
Vest4		0.96
MVP		0.90
MPC		2.2
ClinPred		0.041	T
GERP RS		4.7
Varity_R		0.86
gMVP		0.89

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: rs36031925; hg19: chr8-37822931;