rs56343250

Variant names:

• chr3-148742155-A-T
• rs56343250
• NM_000685.5:c.*40A>T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000685.5(AGTR1):​c.*40A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000998 in 1,609,418 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (5 hom.)
• Consequence: AGTR1 NM_000685.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00104 (159/152320) while in subpopulation NFE AF= 0.00196 (133/68028). AF 95% confidence interval is 0.00168. There are 0 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGTR1	NM_000685.5	c.*40A>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000349243.8	NP_000676.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGTR1	ENST00000349243.8	c.*40A>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_000685.5	ENSP00000273430.3

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 159 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00195

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000880 AC: 220 AN: 249938 Hom.: 1 AF XY: 0.000893 AC XY: 121 AN XY: 135552

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.000993 AC: 1447 AN: 1457098 Hom.: 5 Cov.: 32 AF XY: 0.00102 AC XY: 742 AN XY: 725252

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.000690

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000449

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.000664

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000940 AC XY: 70 AN XY: 74474

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00196

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.000865

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal tubular dysgenesis Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.6
DANN	Benign	0.75

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: rs56343250; hg19: chr3-148459942;