1-230704350-T-C

Position:

• chr1-230704350-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000366667.6(AGT):​c.1098-13A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0878 in 1,613,506 control chromosomes in the GnomAD database, including 8,470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (795 hom., cov: 33)
  • Exomes 𝑓: 0.089 (7675 hom.)
• Consequence: AGT ENST00000366667.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.98

Genes affected

AGT (HGNC:333): (angiotensinogen) The protein encoded by this gene, pre-angiotensinogen or angiotensinogen precursor, is expressed in the liver and is cleaved by the enzyme renin in response to lowered blood pressure. The resulting product, angiotensin I, is then cleaved by angiotensin converting enzyme (ACE) to generate the physiologically active enzyme angiotensin II. The protein is involved in maintaining blood pressure, body fluid and electrolyte homeostasis, and in the pathogenesis of essential hypertension and preeclampsia. Mutations in this gene are associated with susceptibility to essential hypertension, and can cause renal tubular dysgenesis, a severe disorder of renal tubular development. Defects in this gene have also been associated with non-familial structural atrial fibrillation, and inflammatory bowel disease. [provided by RefSeq, Nov 2019]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 1-230704350-T-C is Benign according to our data. Variant chr1-230704350-T-C is described in ClinVar as [Benign]. Clinvar id is 296076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGT	NM_001384479.1	c.1098-13A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000366667.6	NP_001371408.1
AGT	NM_001382817.3	c.1098-13A>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001369746.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGT	ENST00000366667.6	c.1098-13A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001384479.1	ENSP00000355627	P1

Frequencies

GnomAD3 genomes AF: 0.0805 AC: 12249 AN: 152122 Hom.: 795 Cov.: 33

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0423

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0799

Gnomad OTH AF: 0.0728

GnomAD3 exomes AF: 0.112 AC: 28057 AN: 250038 Hom.: 2543 AF XY: 0.107 AC XY: 14443 AN XY: 135198

Gnomad AFR exome AF: 0.0416

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.0313

Gnomad EAS exome AF: 0.351

Gnomad SAS exome AF: 0.0924

Gnomad FIN exome AF: 0.0519

Gnomad NFE exome AF: 0.0787

Gnomad OTH exome AF: 0.0862

GnomAD4 exome AF: 0.0886 AC: 129475 AN: 1461266 Hom.: 7675 Cov.: 32 AF XY: 0.0884 AC XY: 64281 AN XY: 726916

Gnomad4 AFR exome AF: 0.0392

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.0322

Gnomad4 EAS exome AF: 0.329

Gnomad4 SAS exome AF: 0.0955

Gnomad4 FIN exome AF: 0.0534

Gnomad4 NFE exome AF: 0.0795

Gnomad4 OTH exome AF: 0.0904

GnomAD4 genome AF: 0.0805 AC: 12255 AN: 152240 Hom.: 795 Cov.: 33 AF XY: 0.0818 AC XY: 6089 AN XY: 74428

Gnomad4 AFR AF: 0.0412

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.348

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0423

Gnomad4 NFE AF: 0.0799

Gnomad4 OTH AF: 0.0754

Alfa AF: 0.0587 Hom.: 133

Bravo AF: 0.0881

Asia WGS AF: 0.223 AC: 775 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.95
CADD	Benign	0.0060
DANN	Benign	0.36
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: rs1926723; hg19: chr1-230840096; COSMIC: COSV64184131;