chr1-230702974-A-G

Variant names:

• chr1-230702974-A-G
• rs5043
• NM_001384479.1:c.*167T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_001384479.1(AGT):​c.*167T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000665 in 737,220 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: AGT NM_001384479.1 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.861
• Publications: 5 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00194 (295/152236) while in subpopulation AFR AF = 0.00626 (260/41556). AF 95% confidence interval is 0.00563. There are 0 homozygotes in GnomAd4. There are 140 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_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.*167T>C		3_prime_UTR	Exon 5 of 5	NP_001371408.1	P01019
	AGT	NM_001382817.3		c.*167T>C		3_prime_UTR	Exon 5 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.*167T>C		3_prime_UTR	Exon 5 of 5	ENSP00000355627.5	P01019
	AGT	ENST00000680041.1		c.*167T>C		3_prime_UTR	Exon 5 of 5	ENSP00000504866.1	P01019
	AGT	ENST00000681269.1		c.*167T>C		3_prime_UTR	Exon 5 of 5	ENSP00000505985.1	P01019

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 291 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00618

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000333 AC: 195 AN: 584984 Hom.: 0 Cov.: 8 AF XY: 0.000291 AC XY: 88 AN XY: 302892

African (AFR) AF: 0.00642 AC: 97 AN: 15120

American (AMR) AF: 0.000460 AC: 10 AN: 21716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15002

East Asian (EAS) AF: 0.000157 AC: 5 AN: 31766

South Asian (SAS) AF: 0.000936 AC: 46 AN: 49168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2246

European-Non Finnish (NFE) AF: 0.0000128 AC: 5 AN: 389198

Other (OTH) AF: 0.00105 AC: 32 AN: 30500

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152236 Hom.: 0 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74422

African (AFR) AF: 0.00626 AC: 260 AN: 41556

American (AMR) AF: 0.00111 AC: 17 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5146

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00252 Hom.: 0

Bravo AF: 0.00216

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	-0.85
CADD	Benign	0.70
DANN	Benign	0.42
PhyloP100		-0.86
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: rs5043; hg19: chr1-230838720;