rs5042

Variant names:

• chr1-230703101-G-A
• rs5042
• NM_001384479.1:c.*40C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_001382817.3(AGT):​c.*40C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,606,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: AGT NM_001382817.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.345
• Publications: 6 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-230703101-G-A is Benign according to our data. Variant chr1-230703101-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 875822.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0019 (289/152348) while in subpopulation AFR AF = 0.00671 (279/41594). AF 95% confidence interval is 0.00606. There are 0 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGT	NM_001384479.1	MANE Select	c.*40C>T		3_prime_UTR	Exon 5 of 5	NP_001371408.1
	AGT	NM_001382817.3		c.*40C>T		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.*40C>T		3_prime_UTR	Exon 5 of 5	ENSP00000355627.5
	AGT	ENST00000680041.1		c.*40C>T		3_prime_UTR	Exon 5 of 5	ENSP00000504866.1
	AGT	ENST00000681269.1		c.*40C>T		3_prime_UTR	Exon 5 of 5	ENSP00000505985.1

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00673

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000417 AC: 104 AN: 249208 AF XY: 0.000304

Gnomad AFR exome AF: 0.00560

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000208 AC: 302 AN: 1454050 Hom.: 0 Cov.: 30 AF XY: 0.000184 AC XY: 133 AN XY: 723016

African (AFR) AF: 0.00760 AC: 253 AN: 33272

American (AMR) AF: 0.000314 AC: 14 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4318

European-Non Finnish (NFE) AF: 0.0000154 AC: 17 AN: 1106832

Other (OTH) AF: 0.000250 AC: 15 AN: 59990

GnomAD4 genome AF: 0.00190 AC: 289 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.00158 AC XY: 118 AN XY: 74498

African (AFR) AF: 0.00671 AC: 279 AN: 41594

American (AMR) AF: 0.000392 AC: 6 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.00207

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Renal tubular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.5
DANN	Benign	0.87
PhyloP100		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs5042; hg19: chr1-230838847;