1-230710048-A-G

Position:

chr1-230710048-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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 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
NM_001384479.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.514

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
AGT	NM_001384479.1 linkuse as main transcript	c.776T>C	p.Met259Thr	missense_variant	2/5	ENST00000366667.6	NP_001371408.1
AGT	NM_001382817.3 linkuse as main transcript	c.776T>C	p.Met259Thr	missense_variant	2/5		NP_001369746.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGT	ENST00000366667.6 linkuse as main transcript	c.776T>C	p.Met259Thr	missense_variant	2/5	1	NM_001384479.1	ENSP00000355627	P1

Frequencies

GnomAD3 genomes

AF:

0.578

AC:

87869

AN:

152062

Hom.:

27970

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.462

AC XY:

335636

AN XY:

727170

show subpopulations

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.:

AF XY:

0.583

AC XY:

43390

AN XY:

74390

show subpopulations

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

not provided

Benign:3

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Renal tubular dysgenesis

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Hypertensive disorder

Benign:1

Benign, no assertion criteria provided

reference population

iDNA Genomics

Oct 12, 2021

- -

Hypertension, essential, susceptibility to

Benign:1

Benign, 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

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.090

DANN

Benign

0.47

DEOGEN2

Benign

0.21

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0028

LIST_S2

Benign

0.10

MetaRNN

Benign

8.1e-7

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

1.6

REVEL

Benign

0.16

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.024

MPC

0.054

ClinPred

0.0090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over