ENST00000679957.1:c.-217G>A

Variant names:

• chr1-230714272-C-T
• rs11568020
• ENST00000679957.1:c.-217G>A

Variant summary

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

The ENST00000679957.1(AGT):​c.-217G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 152,474 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (161 hom., cov: 32)
  • Exomes 𝑓: 0.043 (0 hom.)
• Consequence: AGT ENST00000679957.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.65
• Publications: 14 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)

CAPN9-AS1 (HGNC:58238):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-230714272-C-T is Benign according to our data. Variant chr1-230714272-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 296094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000679957.1. 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_001382817.3		c.-30-3419G>A		intron	N/A	NP_001369746.2
	AGT	NM_001384479.1	MANE Select	c.-217G>A		upstream_gene	N/A	NP_001371408.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGT	ENST00000679957.1		c.-217G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000506646.1
	AGT	ENST00000679684.1		c.-217G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000505981.1
	AGT	ENST00000680783.1		c.-217G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000506329.1

Frequencies

GnomAD3 genomes AF: 0.0385 AC: 5862 AN: 152168 Hom.: 161 Cov.: 32

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0667

Gnomad ASJ AF: 0.0354

Gnomad EAS AF: 0.0545

Gnomad SAS AF: 0.0416

Gnomad FIN AF: 0.0237

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0413

Gnomad OTH AF: 0.0521

GnomAD4 exome AF: 0.0426 AC: 8 AN: 188 Hom.: 0 Cov.: 0 AF XY: 0.0352 AC XY: 5 AN XY: 142

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 1 AN: 8

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0432 AC: 7 AN: 162

Other (OTH) AF: 0.00 AC: 0 AN: 8

GnomAD4 genome AF: 0.0385 AC: 5867 AN: 152286 Hom.: 161 Cov.: 32 AF XY: 0.0388 AC XY: 2888 AN XY: 74456

African (AFR) AF: 0.0247 AC: 1027 AN: 41574

American (AMR) AF: 0.0668 AC: 1021 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0354 AC: 123 AN: 3472

East Asian (EAS) AF: 0.0544 AC: 281 AN: 5166

South Asian (SAS) AF: 0.0421 AC: 203 AN: 4826

European-Finnish (FIN) AF: 0.0237 AC: 252 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0413 AC: 2811 AN: 68020

Other (OTH) AF: 0.0515 AC: 109 AN: 2116

Alfa AF: 0.0420 Hom.: 262

Bravo AF: 0.0422

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.74
CADD	Benign	0.018
DANN	Benign	0.55
PhyloP100		-2.7
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs11568020; hg19: chr1-230850018;