chr1-230710048-A-G

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_Strong

The NM_001384479.1(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 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 (★★). 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: 1370 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 ACMG Germline Pathogenicity v2019

Our verdict: Benign. The variant received -14 points.

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
• BP6: ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (11/11 total B/LB).
• BA1: GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.8391 — exceeds 5%% threshold (BA1 applied)

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	NP_001371408.1	P01019
	AGT	NM_001382817.3		c.776T>C	p.Met259Thr	missense	Exon 2 of 5	NP_001369746.2	P01019

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGT	ENST00000366667.6	TSL:1 MANE Select	c.776T>C	p.Met259Thr	missense	Exon 2 of 5	ENSP00000355627.5	P01019
	AGT	ENST00000680041.1		c.776T>C	p.Met259Thr	missense	Exon 2 of 5	ENSP00000504866.1	P01019
	AGT	ENST00000681269.1		c.776T>C	p.Met259Thr	missense	Exon 2 of 5	ENSP00000505985.1	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	0.578	87869	27970	152062	33
GnomAD2 exomes	0.548	137772		251344
GnomAD4 exome	0.458	669469	163148	1461692	65
GnomAD4 genome	0.578	87993	28034	152182	33
TOPMed (Bravo)	0.604
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.480	398905	103394	830668
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	0.553	1296	377	2342
ChinaMAP Phase 1	0.811
Denmark Genome	0.333	100		300
ESP6500 (Exome Variant Server)	0.562	7305		13006
GenomeAsia100K	0.729	2532		3478
Korea4K (4,157 Koreans)	0.811	5865		7234
Qatari Genome	0.561	1128		2010
ToMMo 61KJPN (+60KJPN MNV)	0.815	100121	40887	122794
Turkish Variome	0.537	3603	959	6708
UK10K	0.403	3049		7562
WBBC (Westlake BioBank for Chinese) pilot	0.828	7422	3081	8960

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 prediction	Prediction	Score
AlphaGenome AVI	Benign	-	6.2
AlphaMissense	Benign	-	0.054
BayesDel_addAF	Benign	T	-0.63
BayesDel_noAF	Benign	-	-0.54
CADD	Benign	-	0.090
DANN	Benign	-	0.47
DEOGEN2	Benign	T	0.21
Eigen	Benign	-	-1.6
Eigen_PC	Benign	-	-1.5
FATHMM_MKL	Benign	N	0.0028
FuncVEP CTI	Benign	-	0.0091
GPN-Star LLR	N/A	-	2.5
GPN-Star score	N/A	-	-1.5
LIST_S2	Benign	T	0.10
MetaRNN	Benign	T	8.1e-7
MetaSVM	Benign	T	-0.99
Mutation Taster	N/A	polymorphism (auto)	98/2
MutationAssessor	Benign	N	-1.7
PhyloP100	Benign	-	0.51
popEVE	Benign	-	-2.6
PrimateAI	Benign	T	0.26
PROVEAN	Benign	N	1.6
RBP_binding_hub_radar	N/A	-	0.0
RBP_regulation_power_radar	N/A	-	1.1
REVEL	Benign	-	0.16
Sift	Benign	T	1.0
Sift4G	Benign	T	1.0
Varity_R	N/A	-	0.18
VESM-3B	Benign	-	-1.7

Showing 29 of 29 scores

Splicing Scores

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

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.

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