chr3-148698075-C-A

Position:

• chr3-148698075-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000685.5(AGTR1):​c.-184C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00531 in 152,184 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AGTR1 NM_000685.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.100

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 3-148698075-C-A is Benign according to our data. Variant chr3-148698075-C-A is described in ClinVar as [Benign]. Clinvar id is 343666.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00531 (808/152184) while in subpopulation EAS AF= 0.0309 (159/5146). AF 95% confidence interval is 0.027. There are 19 homozygotes in gnomad4. There are 440 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGTR1	NM_000685.5	c.-184C>A		5_prime_UTR_variant	1/3	ENST00000349243.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGTR1	ENST00000349243.8	c.-184C>A		5_prime_UTR_variant	1/3	1	NM_000685.5	P1
AGTR1	ENST00000404754.2	c.-122C>A		5_prime_UTR_variant	1/2	1		P1
AGTR1	ENST00000497524.5	c.-100C>A		5_prime_UTR_variant	1/2	1		P1
AGTR1	ENST00000418473.7	c.-158C>A		5_prime_UTR_variant	1/3	5		P1

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 809 AN: 152076 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.0319

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.0308

Gnomad SAS AF: 0.0254

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.0120

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 46 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 36

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.00531 AC: 808 AN: 152184 Hom.: 19 Cov.: 32 AF XY: 0.00591 AC XY: 440 AN XY: 74404

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.0309

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00286 Hom.: 2

Bravo AF: 0.00509

Asia WGS AF: 0.0310 AC: 107 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.75
CADD	Benign	5.6
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2307085; hg19: chr3-148415862;