3-148741608-C-T

Position:

• chr3-148741608-C-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.573C>T​(p.Leu191Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 1,613,482 control chromosomes in the GnomAD database, including 180,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14558 hom., cov: 32)
  • Exomes 𝑓: 0.47 (166368 hom.)
• Consequence: AGTR1 NM_000685.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.186

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=-0.83).
• BP6: Variant 3-148741608-C-T is Benign according to our data. Variant chr3-148741608-C-T is described in ClinVar as [Benign]. Clinvar id is 256759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-148741608-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.186 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGTR1	NM_000685.5	c.573C>T	p.Leu191Leu	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.573C>T	p.Leu191Leu	synonymous_variant	3/3	1	NM_000685.5	ENSP00000273430.3

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62741 AN: 151880 Hom.: 14550 Cov.: 32

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.402

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.427

GnomAD3 exomes AF: 0.490 AC: 122644 AN: 250128 Hom.: 31577 AF XY: 0.491 AC XY: 66458 AN XY: 135490

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.542

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.702

Gnomad SAS exome AF: 0.488

Gnomad FIN exome AF: 0.585

Gnomad NFE exome AF: 0.472

Gnomad OTH exome AF: 0.474

GnomAD4 exome AF: 0.473 AC: 690764 AN: 1461484 Hom.: 166368 Cov.: 59 AF XY: 0.473 AC XY: 344192 AN XY: 727038

Gnomad4 AFR exome AF: 0.186

Gnomad4 AMR exome AF: 0.537

Gnomad4 ASJ exome AF: 0.402

Gnomad4 EAS exome AF: 0.675

Gnomad4 SAS exome AF: 0.490

Gnomad4 FIN exome AF: 0.580

Gnomad4 NFE exome AF: 0.468

Gnomad4 OTH exome AF: 0.459

GnomAD4 genome AF: 0.413 AC: 62762 AN: 151998 Hom.: 14558 Cov.: 32 AF XY: 0.422 AC XY: 31312 AN XY: 74286

Gnomad4 AFR AF: 0.204

Gnomad4 AMR AF: 0.505

Gnomad4 ASJ AF: 0.402

Gnomad4 EAS AF: 0.685

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.585

Gnomad4 NFE AF: 0.469

Gnomad4 OTH AF: 0.434

Alfa AF: 0.445 Hom.: 15690

Bravo AF: 0.398

Asia WGS AF: 0.575 AC: 1998 AN: 3478

EpiCase AF: 0.452

EpiControl AF: 0.449

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	- -

Renal tubular dysgenesis Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.61

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: rs5182; hg19: chr3-148459395; COSMIC: COSV62559474;