rs5183

Positions:

• chr3-148742097-A-G
• chr3-148742097-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000685.5(AGTR1):​c.1062A>G​(p.Pro354=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0673 in 1,613,898 control chromosomes in the GnomAD database, including 6,107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1976 hom., cov: 32)
  • Exomes 𝑓: 0.062 (4131 hom.)
• Consequence: AGTR1 NM_000685.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.24

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 3-148742097-A-G is Benign according to our data. Variant chr3-148742097-A-G is described in ClinVar as [Benign]. Clinvar id is 256758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-148742097-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGTR1	NM_000685.5	c.1062A>G	p.Pro354=	synonymous_variant	3/3	ENST00000349243.8	NP_000676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGTR1	ENST00000349243.8	c.1062A>G	p.Pro354=	synonymous_variant	3/3	1	NM_000685.5	ENSP00000273430	P1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18214 AN: 151938 Hom.: 1965 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.0552

Gnomad ASJ AF: 0.0302

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0449

Gnomad FIN AF: 0.0784

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0566

Gnomad OTH AF: 0.0883

GnomAD3 exomes AF: 0.0615 AC: 15377 AN: 249974 Hom.: 980 AF XY: 0.0586 AC XY: 7950 AN XY: 135558

Gnomad AFR exome AF: 0.301

Gnomad AMR exome AF: 0.0341

Gnomad ASJ exome AF: 0.0258

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0440

Gnomad FIN exome AF: 0.0694

Gnomad NFE exome AF: 0.0540

Gnomad OTH exome AF: 0.0510

GnomAD4 exome AF: 0.0618 AC: 90319 AN: 1461842 Hom.: 4131 Cov.: 35 AF XY: 0.0605 AC XY: 43998 AN XY: 727234

Gnomad4 AFR exome AF: 0.301

Gnomad4 AMR exome AF: 0.0360

Gnomad4 ASJ exome AF: 0.0275

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0462

Gnomad4 FIN exome AF: 0.0700

Gnomad4 NFE exome AF: 0.0592

Gnomad4 OTH exome AF: 0.0675

GnomAD4 genome AF: 0.120 AC: 18258 AN: 152056 Hom.: 1976 Cov.: 32 AF XY: 0.118 AC XY: 8747 AN XY: 74346

Gnomad4 AFR AF: 0.293

Gnomad4 AMR AF: 0.0550

Gnomad4 ASJ AF: 0.0302

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0439

Gnomad4 FIN AF: 0.0784

Gnomad4 NFE AF: 0.0566

Gnomad4 OTH AF: 0.0874

Alfa AF: 0.0724 Hom.: 992

Bravo AF: 0.128

Asia WGS AF: 0.0310 AC: 106 AN: 3478

EpiCase AF: 0.0569

EpiControl AF: 0.0573

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Renal tubular dysgenesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.011
DANN	Benign	0.30

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: rs5183; hg19: chr3-148459884; COSMIC: COSV62560389;