chr3-148742671-T-C

Variant names:

• chr3-148742671-T-C
• rs12721274
• NM_000685.5:c.*556T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000685.5(AGTR1):​c.*556T>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 0.000453 in 216,178 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00062 (3 hom., cov: 33)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: AGTR1 NM_000685.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0250
• Publications: 1 publications found

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]

AGTR1 Gene-Disease associations (from GenCC):

• renal tubular dysgenesis of genetic origin

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• essential hypertension, genetic

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000624 (95/152320) while in subpopulation AFR AF = 0.000625 (26/41576). AF 95% confidence interval is 0.000438. There are 3 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000685.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTR1	NM_000685.5	MANE Select	c.*556T>C		3_prime_UTR	Exon 3 of 3	NP_000676.1	P30556
	AGTR1	NM_001382736.1		c.*556T>C		3_prime_UTR	Exon 2 of 2	NP_001369665.1	Q53YY0
	AGTR1	NM_001382737.1		c.*556T>C		3_prime_UTR	Exon 3 of 3	NP_001369666.1	P30556

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTR1	ENST00000349243.8	TSL:1 MANE Select	c.*556T>C		3_prime_UTR	Exon 3 of 3	ENSP00000273430.3	P30556
	AGTR1	ENST00000404754.2	TSL:1	c.*556T>C		3_prime_UTR	Exon 2 of 2	ENSP00000385612.2	P30556
	AGTR1	ENST00000497524.5	TSL:1	c.*556T>C		3_prime_UTR	Exon 2 of 2	ENSP00000419422.1	P30556

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152202 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.0000470 AC: 3 AN: 63858 Hom.: 0 Cov.: 0 AF XY: 0.0000309 AC XY: 1 AN XY: 32342

African (AFR) AF: 0.00196 AC: 1 AN: 510

American (AMR) AF: 0.00 AC: 0 AN: 3252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1030

East Asian (EAS) AF: 0.00 AC: 0 AN: 2076

South Asian (SAS) AF: 0.00 AC: 0 AN: 7032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 17072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 180

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 29942

Other (OTH) AF: 0.000724 AC: 2 AN: 2764

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152320 Hom.: 3 Cov.: 33 AF XY: 0.000591 AC XY: 44 AN XY: 74488

African (AFR) AF: 0.000625 AC: 26 AN: 41576

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000922

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Renal tubular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.51
PhyloP100		-0.025

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

Other links and lift over

dbSNP: rs12721274; hg19: chr3-148460458;