rs1216856712

Variant names:

• chr8-37965647-A-C
• rs1216856712
• NM_000025.3:c.823T>G

Your query was ambiguous. Multiple possible variants found:

• chr8-37965647-A-C
• chr8-37965647-A-G
• chr8-37965647-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000025.3(ADRB3):​c.823T>G​(p.Cys275Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000196 in 1,531,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. C275S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADRB3 NM_000025.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.521
• Publications: 0 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]

ENSG00000285880 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06943166).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRB3	NM_000025.3	c.823T>G	p.Cys275Gly	missense_variant	Exon 1 of 2	ENST00000345060.5	NP_000016.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADRB3	ENST00000345060.5	c.823T>G	p.Cys275Gly	missense_variant	Exon 1 of 2	1	NM_000025.3	ENSP00000343782.3
ENSG00000285880	ENST00000647937.1	c.307T>G	p.Cys103Gly	missense_variant	Exon 1 of 2			ENSP00000497740.1
ADRB3	ENST00000520341.2	n.951T>G		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000810 AC: 1 AN: 123392 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1379846 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 679964

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

African (AFR) AF: 0.00 AC: 0 AN: 29068

American (AMR) AF: 0.00 AC: 0 AN: 33912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24544

East Asian (EAS) AF: 0.0000295 AC: 1 AN: 33858

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 77180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5100

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1072024

Other (OTH) AF: 0.00 AC: 0 AN: 57124

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002339), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74286

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.2
DANN	Benign	0.42
DEOGEN2	Benign	0.042	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.20	T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.86	.;N
PhyloP100		-0.52
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.47	.;N
REVEL	Benign	0.043
Sift	Benign	0.34	.;T
Sift4G	Benign	0.45	.;T
Polyphen		0.0	.;B
Vest4		0.043
MutPred		0.43		.;Loss of stability (P = 0.0186);
MVP		0.55
MPC		1.0
ClinPred		0.064	T
GERP RS		-0.49
PromoterAI		0.026	Neutral
Varity_R		0.061
gMVP		0.35
Mutation Taster		=99/1	polymorphism

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: rs1216856712; hg19: chr8-37823165;