chr8-37965350-C-A

Variant names:

• chr8-37965350-C-A
• rs533964715
• NM_000025.3:c.1120G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000025.3(ADRB3):​c.1120G>T​(p.Ala374Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000655 in 1,542,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A374T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: ADRB3 NM_000025.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009585023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRB3	NM_000025.3	c.1120G>T	p.Ala374Ser	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.1120G>T	p.Ala374Ser	missense_variant	Exon 1 of 2	1	NM_000025.3	ENSP00000343782.3
ENSG00000285880	ENST00000647937.1	c.604G>T	p.Ala202Ser	missense_variant	Exon 1 of 2			ENSP00000497740.1
ADRB3	ENST00000520341.2	n.1248G>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000478

GnomAD2 exomes AF: 0.0000734 AC: 10 AN: 136308 AF XY: 0.0000943

Gnomad AFR exome AF: 0.00134

Gnomad AMR exome AF: 0.0000894

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: 0.0000439 AC: 61 AN: 1390232 Hom.: 0 Cov.: 31 AF XY: 0.0000438 AC XY: 30 AN XY: 685540

African (AFR) AF: 0.00149 AC: 46 AN: 30850

American (AMR) AF: 0.0000594 AC: 2 AN: 33678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24832

East Asian (EAS) AF: 0.00 AC: 0 AN: 35480

South Asian (SAS) AF: 0.0000127 AC: 1 AN: 78572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47770

Middle Eastern (MID) AF: 0.000406 AC: 2 AN: 4930

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076622

Other (OTH) AF: 0.000157 AC: 9 AN: 57498

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152168 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74332

African (AFR) AF: 0.000893 AC: 37 AN: 41448

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.000280

ExAC AF: 0.0000582 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1120G>T (p.A374S) alteration is located in exon 1 (coding exon 1) of the ADRB3 gene. This alteration results from a G to T substitution at nucleotide position 1120, causing the alanine (A) at amino acid position 374 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.0
DANN	Uncertain	0.98
DEOGEN2	Benign	0.045	.;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.41	T;T
M_CAP	Benign	0.085	D
MetaRNN	Benign	0.0096	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	.;M
PhyloP100		1.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.31	.;N
REVEL	Benign	0.028
Sift	Benign	0.14	.;T
Sift4G	Benign	0.56	.;T
Polyphen		0.12	.;B
Vest4		0.20
MutPred		0.19		.;Gain of phosphorylation at A374 (P = 0.0201);
MVP		0.64
MPC		0.97
ClinPred		0.013	T
GERP RS		2.3
Varity_R		0.059
gMVP		0.29
Mutation Taster		=96/4	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: rs533964715; hg19: chr8-37822868; COSMIC: COSV61461644;