rs4762

Positions:

chr1-230710231-G-A

Variant summary

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

The NM_001384479.1(AGT):c.593C>T(p.Thr198Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 1,613,596 control chromosomes in the GnomAD database, including 12,433 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T198T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.11 ( 1080 hom., cov: 33)

Exomes 𝑓: 0.12 ( 11353 hom. )

Consequence

AGT
NM_001384479.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.38

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:

AGT (HGNC:):

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=0.0024677217).

BP6

Variant 1-230710231-G-A is Benign according to our data. Variant chr1-230710231-G-A is described in ClinVar as [Benign]. Clinvar id is 296083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.123 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.593C>T	p.Thr198Met	missense_variant	2/5	ENST00000366667.6	NP_001371408.1
AGT	NM_001382817.3 linkuse as main transcript	c.593C>T	p.Thr198Met	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.593C>T	p.Thr198Met	missense_variant	2/5	1	NM_001384479.1	ENSP00000355627.5		P01019

Frequencies

GnomAD3 genomes

AF:

0.112

AC:

17040

AN:

152154

Hom.:

1082

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0647

Gnomad AMI

AF:

0.224

Gnomad AMR

AF:

0.111

Gnomad ASJ

AF:

0.141

Gnomad EAS

AF:

0.105

Gnomad SAS

AF:

0.131

Gnomad FIN

AF:

0.193

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.125

Gnomad OTH

AF:

0.104

GnomAD3 exomes

AF:

0.124

AC:

31006

AN:

249646

Hom.:

2077

AF XY:

0.124

AC XY:

16806

AN XY:

135222

show subpopulations

Gnomad AFR exome

AF:

0.0618

Gnomad AMR exome

AF:

0.124

Gnomad ASJ exome

AF:

0.139

Gnomad EAS exome

AF:

0.105

Gnomad SAS exome

AF:

0.127

Gnomad FIN exome

AF:

0.179

Gnomad NFE exome

AF:

0.124

Gnomad OTH exome

AF:

0.128

GnomAD4 exome

AF:

0.123

AC:

179076

AN:

1461324

Hom.:

11353

Cov.:

AF XY:

0.123

AC XY:

89491

AN XY:

726958

show subpopulations

Gnomad4 AFR exome

AF:

0.0612

Gnomad4 AMR exome

AF:

0.122

Gnomad4 ASJ exome

AF:

0.138

Gnomad4 EAS exome

AF:

0.104

Gnomad4 SAS exome

AF:

0.128

Gnomad4 FIN exome

AF:

0.173

Gnomad4 NFE exome

AF:

0.122

Gnomad4 OTH exome

AF:

0.116

GnomAD4 genome

AF:

0.112

AC:

17033

AN:

152272

Hom.:

1080

Cov.:

AF XY:

0.115

AC XY:

8532

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0645

Gnomad4 AMR

AF:

0.111

Gnomad4 ASJ

AF:

0.141

Gnomad4 EAS

AF:

0.105

Gnomad4 SAS

AF:

0.129

Gnomad4 FIN

AF:

0.193

Gnomad4 NFE

AF:

0.125

Gnomad4 OTH

AF:

0.104

Alfa

AF:

0.121

Hom.:

2634

Bravo

AF:

0.103

TwinsUK

AF:

0.123

AC:

456

ALSPAC

AF:

0.121

AC:

466

ESP6500AA

AF:

0.0660

AC:

291

ESP6500EA

AF:

0.131

AC:

1130

ExAC

AF:

0.122

AC:

14829

Asia WGS

AF:

0.0990

AC:

342

AN:

3478

EpiCase

AF:

0.123

EpiControl

AF:

0.121

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 25966146, 1394429, 20702504, 17145981, 20854100) -

Renal tubular dysgenesis

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.61

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.8

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.32

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.17

MPC

0.34

ClinPred

0.021

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.48

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