1-230710048-A-G

Variant names:

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

Variant summary

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

The NM_001382817.3(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. 16/21 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_001382817.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.514
• Publications: 1356 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=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 VariationId is 18068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.823 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382817.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

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

Ensembl Transcripts

Selected	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
	AGT	ENST00000680041.1		c.776T>C	p.Met259Thr	missense	Exon 2 of 5	ENSP00000504866.1
	AGT	ENST00000681269.1		c.776T>C	p.Met259Thr	missense	Exon 2 of 5	ENSP00000505985.1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87869 AN: 152062 Hom.: 27970 Cov.: 33

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

GnomAD2 exomes AF: 0.548 AC: 137772 AN: 251344 AF XY: 0.536

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 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.: 65 AF XY: 0.462 AC XY: 335636 AN XY: 727170

African (AFR) AF: 0.847 AC: 28371 AN: 33480

American (AMR) AF: 0.709 AC: 31723 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 11332 AN: 26134

East Asian (EAS) AF: 0.825 AC: 32760 AN: 39698

South Asian (SAS) AF: 0.615 AC: 53082 AN: 86250

European-Finnish (FIN) AF: 0.436 AC: 23270 AN: 53312

Middle Eastern (MID) AF: 0.535 AC: 3088 AN: 5768

European-Non Finnish (NFE) AF: 0.410 AC: 455815 AN: 1111932

Other (OTH) AF: 0.497 AC: 30028 AN: 60394

GnomAD4 genome AF: 0.578 AC: 87993 AN: 152182 Hom.: 28034 Cov.: 33 AF XY: 0.583 AC XY: 43390 AN XY: 74390

African (AFR) AF: 0.830 AC: 34498 AN: 41542

American (AMR) AF: 0.632 AC: 9673 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1490 AN: 3468

East Asian (EAS) AF: 0.832 AC: 4287 AN: 5154

South Asian (SAS) AF: 0.622 AC: 3003 AN: 4830

European-Finnish (FIN) AF: 0.447 AC: 4733 AN: 10590

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28599 AN: 67976

Other (OTH) AF: 0.553 AC: 1169 AN: 2114

Alfa AF: 0.474 Hom.: 91799

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
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
LIST_S2	Benign	0.10	T
MetaRNN	Benign	8.1e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.7	N
PhyloP100		0.51
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.054
ClinPred		0.0090	T
GERP RS		-0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.14
Mutation Taster		=98/2	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: rs699; hg19: chr1-230845794; COSMIC: COSV64184214; COSMIC: COSV64184214;