NM_000684.3:c.1165G>C

Variant names:

• chr10-114045297-G-C
• rs1801253
• NM_000684.3:c.1165G>C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000684.3(ADRB1):​c.1165G>C​(p.Gly389Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 1,577,268 control chromosomes in the GnomAD database, including 423,077 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,association (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G389V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.70 (36948 hom., cov: 34)
  • Exomes 𝑓: 0.73 (386129 hom.)
• Consequence: ADRB1 NM_000684.3 missense
• Clinical Significance: Benign; association no assertion criteria provided B:2 O:1
• Conservation: PhyloP100: 1.04

Genes affected

ADRB1 (HGNC:285): (adrenoceptor beta 1) The adrenergic receptors (subtypes alpha 1, alpha 2, beta 1, and beta 2) are a prototypic family of guanine nucleotide binding regulatory protein-coupled receptors that mediate the physiological effects of the hormone epinephrine and the neurotransmitter norepinephrine. Beta-1 adrenoceptors are predominately located in the heart. Specific polymorphisms in this gene have been shown to affect the resting heart rate and can be involved in heart failure. [provided by RefSeq, Sep 2019]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.993127E-7).
• BP6: Variant 10-114045297-G-C is Benign according to our data. Variant chr10-114045297-G-C is described in ClinVar as [Benign, association]. Clinvar id is 17746.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.765 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADRB1	NM_000684.3	c.1165G>C	p.Gly389Arg	missense_variant	Exon 1 of 1	ENST00000369295.4	NP_000675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADRB1	ENST00000369295.4	c.1165G>C	p.Gly389Arg	missense_variant	Exon 1 of 1	6	NM_000684.3	ENSP00000358301.2

Frequencies

GnomAD3 genomes AF: 0.696 AC: 104769 AN: 150514 Hom.: 36905 Cov.: 34

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.621

Gnomad EAS AF: 0.763

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.743

Gnomad MID AF: 0.624

Gnomad NFE AF: 0.732

Gnomad OTH AF: 0.681

GnomAD3 exomes AF: 0.737 AC: 162149 AN: 219864 Hom.: 60356 AF XY: 0.735 AC XY: 89178 AN XY: 121330

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.859

Gnomad ASJ exome AF: 0.625

Gnomad EAS exome AF: 0.745

Gnomad SAS exome AF: 0.754

Gnomad FIN exome AF: 0.739

Gnomad NFE exome AF: 0.725

Gnomad OTH exome AF: 0.717

GnomAD4 exome AF: 0.734 AC: 1047689 AN: 1426646 Hom.: 386129 Cov.: 58 AF XY: 0.735 AC XY: 521652 AN XY: 709768

Gnomad4 AFR exome AF: 0.579

Gnomad4 AMR exome AF: 0.846

Gnomad4 ASJ exome AF: 0.620

Gnomad4 EAS exome AF: 0.781

Gnomad4 SAS exome AF: 0.755

Gnomad4 FIN exome AF: 0.746

Gnomad4 NFE exome AF: 0.735

Gnomad4 OTH exome AF: 0.720

GnomAD4 genome AF: 0.696 AC: 104861 AN: 150622 Hom.: 36948 Cov.: 34 AF XY: 0.699 AC XY: 51435 AN XY: 73560

Gnomad4 AFR AF: 0.593

Gnomad4 AMR AF: 0.777

Gnomad4 ASJ AF: 0.621

Gnomad4 EAS AF: 0.763

Gnomad4 SAS AF: 0.738

Gnomad4 FIN AF: 0.743

Gnomad4 NFE AF: 0.732

Gnomad4 OTH AF: 0.681

Alfa AF: 0.709 Hom.: 12411

Bravo AF: 0.693

TwinsUK AF: 0.724 AC: 2685

ALSPAC AF: 0.752 AC: 2897

ESP6500AA AF: 0.627 AC: 2565

ESP6500EA AF: 0.736 AC: 5915

ExAC AF: 0.727 AC: 85629

Asia WGS AF: 0.732 AC: 2456 AN: 3356

ClinVar

Significance: Benign; association

Submissions summary: Benign:2 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

ADRB1-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Apr 01, 2007

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pulmonary disease, chronic obstructive, susceptibility to Other:1

Jul 05, 2022

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: association

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.66
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.34	N
MetaRNN	Benign	8.0e-7	T
MetaSVM	Benign	-0.96	T
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	3.2	N
REVEL	Benign	0.070
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.055
MutPred		0.32		Gain of MoRF binding (P = 0.02);
ClinPred		0.0049	T
GERP RS		1.7
gMVP		0.54

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: rs1801253; hg19: chr10-115805056; COSMIC: COSV65167813;