AGT Met259Thr

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.776T>C(p.Met259Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,613,874 control chromosomes in the GnomAD database, including 191,182 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (28034 hom., cov: 33)
  • Exomes 𝑓: 0.46 (163148 hom.)
• Consequence: AGT ENST00000366667.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:3
• Conservation: PhyloP100: 0.514

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 (MetaRNN=8.121765E-7).
• BP6: Variant 1-230710048-A-G is Benign according to our data. Variant chr1-230710048-A-G is described in ClinVar as [Benign]. Clinvar id is 18068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-230710048-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGT	NM_001384479.1	c.776T>C	p.Met259Thr	missense_variant	2/5	ENST00000366667.6
AGT	NM_001382817.3	c.776T>C	p.Met259Thr	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGT	ENST00000366667.6	c.776T>C	p.Met259Thr	missense_variant	2/5	1	NM_001384479.1	P1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87869 AN: 152062 Hom.: 27970 Cov.: 33

Gnomad AFR AF: 0.830

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.631

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.833

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.548

GnomAD3 exomes AF: 0.548 AC: 137772 AN: 251344 Hom.: 41270 AF XY: 0.536 AC XY: 72890 AN XY: 135888

Gnomad AFR exome AF: 0.845

Gnomad AMR exome AF: 0.720

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.839

Gnomad SAS exome AF: 0.620

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.420

Gnomad OTH exome AF: 0.500

GnomAD4 exome AF: 0.458 AC: 669469 AN: 1461692 Hom.: 163148 Cov.: 65 AF XY: 0.462 AC XY: 335636 AN XY: 727170

Gnomad4 AFR exome AF: 0.847

Gnomad4 AMR exome AF: 0.709

Gnomad4 ASJ exome AF: 0.434

Gnomad4 EAS exome AF: 0.825

Gnomad4 SAS exome AF: 0.615

Gnomad4 FIN exome AF: 0.436

Gnomad4 NFE exome AF: 0.410

Gnomad4 OTH exome AF: 0.497

GnomAD4 genome AF: 0.578 AC: 87993 AN: 152182 Hom.: 28034 Cov.: 33 AF XY: 0.583 AC XY: 43390 AN XY: 74390

Gnomad4 AFR AF: 0.830

Gnomad4 AMR AF: 0.632

Gnomad4 ASJ AF: 0.430

Gnomad4 EAS AF: 0.832

Gnomad4 SAS AF: 0.622

Gnomad4 FIN AF: 0.447

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.553

Alfa AF: 0.455 Hom.: 41273

Bravo AF: 0.604

TwinsUK AF: 0.411 AC: 1525

ALSPAC AF: 0.395 AC: 1524

ESP6500AA AF: 0.827 AC: 3643

ESP6500EA AF: 0.426 AC: 3662

ExAC AF: 0.548 AC: 66560

Asia WGS AF: 0.729 AC: 2532 AN: 3478

EpiCase AF: 0.426

EpiControl AF: 0.424

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Renal tubular dysgenesis Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hypertensive disorder Benign:1

Benign, no assertion criteria provided

reference population

iDNA Genomics

Oct 12, 2021

- -

Preeclampsia, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

Hypertension, essential, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

Susceptibility to progression to renal failure in IgA nephropathy Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jan 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	0.090
DANN	Benign	0.47
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	8.1e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.7	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.054
ClinPred		0.0090	T
GERP RS		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.14

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: rs699; hg19: chr1-230845794; COSMIC: COSV64184214; COSMIC: COSV64184214;