1-230710231-G-A

Variant names:

• chr1-230710231-G-A
• rs4762
• NM_001384479.1:c.593C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.38
• Publications: 353 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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGT	NM_001384479.1	MANE Select	c.593C>T	p.Thr198Met	missense	Exon 2 of 5	NP_001371408.1	P01019
	AGT	NM_001382817.3		c.593C>T	p.Thr198Met	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.593C>T	p.Thr198Met	missense	Exon 2 of 5	ENSP00000355627.5	P01019
	AGT	ENST00000680041.1		c.593C>T	p.Thr198Met	missense	Exon 2 of 5	ENSP00000504866.1	P01019
	AGT	ENST00000681269.1		c.593C>T	p.Thr198Met	missense	Exon 2 of 5	ENSP00000505985.1	P01019

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17040 AN: 152154 Hom.: 1082 Cov.: 33

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

GnomAD2 exomes AF: 0.124 AC: 31006 AN: 249646 AF XY: 0.124

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 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.: 38 AF XY: 0.123 AC XY: 89491 AN XY: 726958

African (AFR) AF: 0.0612 AC: 2049 AN: 33480

American (AMR) AF: 0.122 AC: 5463 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3601 AN: 26136

East Asian (EAS) AF: 0.104 AC: 4133 AN: 39700

South Asian (SAS) AF: 0.128 AC: 11075 AN: 86258

European-Finnish (FIN) AF: 0.173 AC: 9140 AN: 52890

Middle Eastern (MID) AF: 0.112 AC: 644 AN: 5768

European-Non Finnish (NFE) AF: 0.122 AC: 135939 AN: 1111986

Other (OTH) AF: 0.116 AC: 7032 AN: 60388

GnomAD4 genome AF: 0.112 AC: 17033 AN: 152272 Hom.: 1080 Cov.: 33 AF XY: 0.115 AC XY: 8532 AN XY: 74458

African (AFR) AF: 0.0645 AC: 2681 AN: 41568

American (AMR) AF: 0.111 AC: 1706 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 490 AN: 3472

East Asian (EAS) AF: 0.105 AC: 544 AN: 5174

South Asian (SAS) AF: 0.129 AC: 623 AN: 4822

European-Finnish (FIN) AF: 0.193 AC: 2053 AN: 10614

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8488 AN: 67996

Other (OTH) AF: 0.104 AC: 219 AN: 2110

Alfa AF: 0.118 Hom.: 3379

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Renal tubular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.17
MPC		0.34
ClinPred		0.021	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.48
Mutation Taster		=88/12	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4762; hg19: chr1-230845977; COSMIC: COSV64184219; COSMIC: COSV64184219;