1-230702983-G-C

Variant names:

• chr1-230702983-G-C
• rs4753
• NM_001384479.1:c.*158C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001384479.1(AGT):​c.*158C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 796,820 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (17 hom.)
• Consequence: AGT NM_001384479.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.28
• Publications: 7 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 (BayesDel_noAF=-0.83).
• BP6: Variant 1-230702983-G-C is Benign according to our data. Variant chr1-230702983-G-C is described in ClinVar as Benign. ClinVar VariationId is 875821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00693 (1054/152140) while in subpopulation AFR AF = 0.0196 (813/41526). AF 95% confidence interval is 0.0185. There are 7 homozygotes in GnomAd4. There are 520 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.*158C>G		3_prime_UTR	Exon 5 of 5	NP_001371408.1
	AGT	NM_001382817.3		c.*158C>G		3_prime_UTR	Exon 5 of 5	NP_001369746.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGT	ENST00000366667.6	TSL:1 MANE Select	c.*158C>G		3_prime_UTR	Exon 5 of 5	ENSP00000355627.5
	AGT	ENST00000680041.1		c.*158C>G		3_prime_UTR	Exon 5 of 5	ENSP00000504866.1
	AGT	ENST00000681269.1		c.*158C>G		3_prime_UTR	Exon 5 of 5	ENSP00000505985.1

Frequencies

GnomAD3 genomes AF: 0.00689 AC: 1047 AN: 152022 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00233

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00241 AC: 1553 AN: 644680 Hom.: 17 Cov.: 9 AF XY: 0.00282 AC XY: 933 AN XY: 331336

African (AFR) AF: 0.0183 AC: 298 AN: 16248

American (AMR) AF: 0.00230 AC: 51 AN: 22160

Ashkenazi Jewish (ASJ) AF: 0.000836 AC: 13 AN: 15552

East Asian (EAS) AF: 0.000592 AC: 19 AN: 32082

South Asian (SAS) AF: 0.0135 AC: 685 AN: 50714

European-Finnish (FIN) AF: 0.000486 AC: 15 AN: 30852

Middle Eastern (MID) AF: 0.0131 AC: 31 AN: 2370

European-Non Finnish (NFE) AF: 0.000801 AC: 354 AN: 442182

Other (OTH) AF: 0.00268 AC: 87 AN: 32520

GnomAD4 genome AF: 0.00693 AC: 1054 AN: 152140 Hom.: 7 Cov.: 33 AF XY: 0.00699 AC XY: 520 AN XY: 74360

African (AFR) AF: 0.0196 AC: 813 AN: 41526

American (AMR) AF: 0.00373 AC: 57 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00234 AC: 12 AN: 5136

South Asian (SAS) AF: 0.0147 AC: 71 AN: 4816

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00112 AC: 76 AN: 67998

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.000140 Hom.: 0

Bravo AF: 0.00708

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.058
DANN	Benign	0.45
PhyloP100		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs4753; hg19: chr1-230838729;