rs1801252

Positions:

• chr10-114044277-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000684.3(ADRB1):​c.145A>G​(p.Ser49Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,542,848 control chromosomes in the GnomAD database, including 15,863 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.17 (2334 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13529 hom.)
• Consequence: ADRB1 NM_000684.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.0190

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041767657).
• BP6: Variant 10-114044277-A-G is Benign according to our data. Variant chr10-114044277-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 17747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADRB1	NM_000684.3	c.145A>G	p.Ser49Gly	missense_variant	1/1	ENST00000369295.4	NP_000675.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADRB1	ENST00000369295.4	c.145A>G	p.Ser49Gly	missense_variant	1/1		NM_000684.3	ENSP00000358301	P1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25425 AN: 151864 Hom.: 2319 Cov.: 32

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.0905

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.175

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.150

GnomAD3 exomes AF: 0.154 AC: 25769 AN: 167050 Hom.: 2300 AF XY: 0.145 AC XY: 13753 AN XY: 94768

Gnomad AFR exome AF: 0.217

Gnomad AMR exome AF: 0.285

Gnomad ASJ exome AF: 0.0778

Gnomad EAS exome AF: 0.140

Gnomad SAS exome AF: 0.128

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.125

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.134 AC: 186879 AN: 1390870 Hom.: 13529 Cov.: 31 AF XY: 0.133 AC XY: 92056 AN XY: 691118

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.275

Gnomad4 ASJ exome AF: 0.0867

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.135

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.138

GnomAD4 genome AF: 0.168 AC: 25487 AN: 151978 Hom.: 2334 Cov.: 32 AF XY: 0.168 AC XY: 12513 AN XY: 74294

Gnomad4 AFR AF: 0.228

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.0905

Gnomad4 EAS AF: 0.147

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.175

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.149

Alfa AF: 0.134 Hom.: 703

Bravo AF: 0.175

TwinsUK AF: 0.127 AC: 472

ALSPAC AF: 0.141 AC: 545

ESP6500AA AF: 0.194 AC: 828

ESP6500EA AF: 0.108 AC: 905

ExAC AF: 0.145 AC: 17331

Asia WGS AF: 0.159 AC: 549 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

ADRB1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

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

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Resting heart rate Other:1

association, no assertion criteria provided

literature only

OMIM

May 18, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.9
DANN	Benign	0.12
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0050	N
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.040
Sift	Benign	0.81	T
Sift4G	Benign	0.42	T
Vest4		0.011
ClinPred		0.0032	T
GERP RS		1.5
gMVP		0.13

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: rs1801252; hg19: chr10-115804036; COSMIC: COSV65168046;