rs5186

chr3-148742201-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000685.5(AGTR1):c.*86A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,538,798 control chromosomes in the GnomAD database, including 58,749 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4182 hom., cov: 32)
  • Exomes 𝑓: 0.27 (54567 hom.)
• Consequence: AGTR1 NM_000685.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 1.07

Genes affected

AGTR1 (HGNC:336): (angiotensin II receptor type 1) Angiotensin II is a potent vasopressor hormone and a primary regulator of aldosterone secretion. It is an important effector controlling blood pressure and volume in the cardiovascular system. It acts through at least two types of receptors. This gene encodes the type 1 receptor which is thought to mediate the major cardiovascular effects of angiotensin II. This gene may play a role in the generation of reperfusion arrhythmias following restoration of blood flow to ischemic or infarcted myocardium. It was previously thought that a related gene, denoted as AGTR1B, existed; however, it is now believed that there is only one type 1 receptor gene in humans. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGTR1	NM_000685.5	c.*86A>C		3_prime_UTR_variant	3/3	ENST00000349243.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGTR1	ENST00000349243.8	c.*86A>C		3_prime_UTR_variant	3/3	1	NM_000685.5	P1

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31344 AN: 152074 Hom.: 4181 Cov.: 32

Gnomad AFR AF: 0.0625

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.0566

Gnomad SAS AF: 0.0807

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.225

GnomAD3 exomes AF: 0.227 AC: 56561 AN: 248638 Hom.: 7763 AF XY: 0.223 AC XY: 30159 AN XY: 135076

Gnomad AFR exome AF: 0.0578

Gnomad AMR exome AF: 0.300

Gnomad ASJ exome AF: 0.308

Gnomad EAS exome AF: 0.0566

Gnomad SAS exome AF: 0.0895

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.258

GnomAD4 exome AF: 0.269 AC: 373676 AN: 1386606 Hom.: 54567 Cov.: 24 AF XY: 0.264 AC XY: 183361 AN XY: 694336

Gnomad4 AFR exome AF: 0.0544

Gnomad4 AMR exome AF: 0.295

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.0704

Gnomad4 SAS exome AF: 0.0920

Gnomad4 FIN exome AF: 0.196

Gnomad4 NFE exome AF: 0.301

Gnomad4 OTH exome AF: 0.246

GnomAD4 genome AF: 0.206 AC: 31351 AN: 152192 Hom.: 4182 Cov.: 32 AF XY: 0.199 AC XY: 14781 AN XY: 74406

Gnomad4 AFR AF: 0.0623

Gnomad4 AMR AF: 0.258

Gnomad4 ASJ AF: 0.322

Gnomad4 EAS AF: 0.0569

Gnomad4 SAS AF: 0.0804

Gnomad4 FIN AF: 0.179

Gnomad4 NFE AF: 0.296

Gnomad4 OTH AF: 0.223

Alfa AF: 0.275 Hom.: 10274

Bravo AF: 0.212

Asia WGS AF: 0.0770 AC: 266 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal tubular dysgenesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Renal tubular dysgenesis of genetic origin;CN305331:Essential hypertension, genetic Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 16, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2021

This variant is associated with the following publications: (PMID: 17668390, 22237156, 21638051, 20525211, 19021695, 22475523, 18985387, 20703234, 19236533, 19620885, 21799445, 17588946, 21771600, 20026870, 21436209, 22392878, 20594303, 20361261, 21657802, 25603901, 22664914, 8021009, 23615648, 30920415, 27016615, 26283679) -

Hypertension, essential, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.6
Dann	Benign	0.67

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: rs5186; hg19: chr3-148459988;