AGT Met259Thr

Variant names:

• chr1-230710048-A-G
• rs699
• NM_001384479.1:c.776T>C
• AGT p.Met259Thr

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACGS-UK Somatic Oncogenicity v2025). O4_SupportingB1_StrongB3_Supporting

The NM_001384479.1(AGT):c.776T>C (p.Met259Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene AGT is a tumor suppressor gene (CancerMine: 1 TSG, 1 oncogene, 1 driver citations). The gene AGT is a known oncogene (CancerMine: 1 TSG, 1 oncogene, 1 driver citations). The gene AGT is a cancer driver gene (CancerMine: 1 TSG, 1 oncogene, 1 driver citations). The variant allele was found at a cumulative frequency of 0.469 (AC=757,462) in the gnomAD database across 1,613,874 control chromosomes, including 191,182 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.839. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). The variant has been observed in cBioPortal in 9 samples across 8 studies and 7 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.). This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.58 (28034 hom., cov: 33)
  • Exomes 𝑓: 0.46 (163148 hom.)
• Consequence: AGT NM_001384479.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.514
• Publications: 1096 publications found

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]

AGT Gene-Disease associations (from GenCC):

• renal tubular dysgenesis of genetic origin

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=9 | studies=8 | cancer types=7 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.839 — exceeds 1% threshold (B1 applied)
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001384479.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AGT NM_001384479.1	MANE Select	c.776T>C p.Met259Thr	missense	Exon 2 of 5	Prot: NP_001371408.1 UniProt:
	AGT NM_001382817.3		c.776T>C p.Met259Thr	missense	Exon 2 of 5	Prot: NP_001369746.2 UniProt:

AGT NM_001384479.1

MANE Select

HGVSc / HGVSpc.776T>Cp.Met259Thr

Exon rankExon 2 of 5

missense

Prot: NP_001371408.1UniProt: P01019A0A7P0T8D1

AGT NM_001382817.3

HGVSc / HGVSpc.776T>Cp.Met259Thr

Exon rankExon 2 of 5

missense

Prot: NP_001369746.2UniProt: P01019A0A7P0T8D1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AGT ENST00000366667.6	TSL:1MANE Select	c.776T>C p.Met259Thr	missense	Exon 2 of 5	Prot: ENSP00000355627.5 UniProt:
	AGT ENST00000680041.1		c.776T>C p.Met259Thr	missense	Exon 2 of 5	Prot: ENSP00000504866.1 UniProt:
	AGT ENST00000681269.1		c.776T>C p.Met259Thr	missense	Exon 2 of 5	Prot: ENSP00000505985.1 UniProt:

AGT ENST00000366667.6

TSL:1MANE Select

HGVSc / HGVSpc.776T>Cp.Met259Thr

Exon rankExon 2 of 5

missense

Prot: ENSP00000355627.5UniProt: P01019

AGT ENST00000680041.1

HGVSc / HGVSpc.776T>Cp.Met259Thr

Exon rankExon 2 of 5

missense

Prot: ENSP00000504866.1UniProt: P01019

AGT ENST00000681269.1

HGVSc / HGVSpc.776T>Cp.Met259Thr

Exon rankExon 2 of 5

missense

Prot: ENSP00000505985.1UniProt: P01019

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.578	AC:87869	Hom:27970	AN:152062	Cov:33
GnomAD2 exomes	AF: 0.548	AC:137772	Hom:	AN:251344	Cov:
GnomAD4 exome	AF: 0.458	AC:669469	Hom:163148	AN:1461692	Cov:65
GnomAD4 genome	AF: 0.578	AC:87993	Hom:28034	AN:152182	Cov:33
TOPMed (Bravo)	AF: 0.604	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.480	AC:398905	Hom:103394	AN:830668	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.553	AC:1296	Hom:377	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.811	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.333	AC:100	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.562	AC:7305	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.729	AC:2532	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.811	AC:5865	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.561	AC:1128	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.815	AC:100121	Hom:40887	AN:122794	Cov:
Turkish Variome	AF: 0.537	AC:3603	Hom:959	AN:6708	Cov:
UK10K	AF: 0.403	AC:3049	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.828	AC:7422	Hom:3081	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.387 *	3716	9592	0.403 *	4186	10396
BipEx(Bipolar disorder (including schizoaffective))	0.420	11941	28420	0.412	11879	28844
Epi25(Epilepsy)	0.502	21049	41958	0.495	33101	66888
SCHEMA(Schizophrenia)	0.605	93878	155126	0.595	148020	248690

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Renal tubular dysgenesis (2)
-	-	1	Hypertension, essential, susceptibility to (1)
-	-	1	Hypertensive disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	6.2
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
FuncVEP CTI	Benign	0.0091
GPN-Star LLR	N/A	2.5
GPN-Star score	N/A	-1.5
LIST_S2	Benign	0.10	T
MetaRNN	Benign	8.1e-7	T
MetaSVM	Benign	-0.99	T
Mutation Taster	N/A	98/2	polymorphism (auto)
MutationAssessor	Benign	-1.7	N
PhyloP100	Benign	0.51
popEVE	Benign	-2.6
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.6	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R	N/A	0.18
VESM-3B	Benign	-1.7

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs699;

hg19: chr1-230845794;

COSMIC: COSV64184214;

COSMIC: COSV64184214;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar