3-148742250-C-T

Position:

• chr3-148742250-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000685.5(AGTR1):​c.*135C>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 0.00301 in 1,257,812 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (56 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (34 hom.)
• Consequence: AGTR1 NM_000685.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.701

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-148742250-C-T is Benign according to our data. Variant chr3-148742250-C-T is described in ClinVar as [Benign]. Clinvar id is 343678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0134 (2046/152312) while in subpopulation AFR AF= 0.0444 (1844/41562). AF 95% confidence interval is 0.0427. There are 56 homozygotes in gnomad4. There are 958 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGTR1	NM_000685.5	c.*135C>T		3_prime_UTR_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.*135C>T		3_prime_UTR_variant	3/3	1	NM_000685.5	ENSP00000273430.3

Frequencies

GnomAD3 genomes AF: 0.0134 AC: 2037 AN: 152194 Hom.: 56 Cov.: 33

Gnomad AFR AF: 0.0443

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00331 AC: 809 AN: 244568 Hom.: 15 AF XY: 0.00262 AC XY: 350 AN XY: 133422

Gnomad AFR exome AF: 0.0456

Gnomad AMR exome AF: 0.00242

Gnomad ASJ exome AF: 0.000201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.000605

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00285

GnomAD4 exome AF: 0.00157 AC: 1741 AN: 1105500 Hom.: 34 Cov.: 16 AF XY: 0.00140 AC XY: 793 AN XY: 566056

Gnomad4 AFR exome AF: 0.0463

Gnomad4 AMR exome AF: 0.00274

Gnomad4 ASJ exome AF: 0.000167

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000638

Gnomad4 FIN exome AF: 0.000701

Gnomad4 NFE exome AF: 0.000207

Gnomad4 OTH exome AF: 0.00370

GnomAD4 genome AF: 0.0134 AC: 2046 AN: 152312 Hom.: 56 Cov.: 33 AF XY: 0.0129 AC XY: 958 AN XY: 74484

Gnomad4 AFR AF: 0.0444

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00983 Hom.: 11

Bravo AF: 0.0151

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Renal tubular dysgenesis Benign:1

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.36
DANN	Benign	0.50

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: rs1799870; hg19: chr3-148460037;