chr1-230710021-G-A

Variant names:

• chr1-230710021-G-A
• rs1228544607
• NM_001384479.1:c.803C>T
• AGT p.Ala268Val

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+1 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2BP4

The NM_001384479.1(AGT):c.803C>T (p.Ala268Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000684 (AC=10) in the gnomAD database across 1,461,848 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000455. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.A268D: Uncertain_significance (ClinVar VariationId 2328349, 1 star)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: AGT NM_001384479.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.30
• Publications: 3 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), PanelApp Australia

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Uncertain_significance. The variant received 1 points.

• PM2: Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000455 — very rare for AR gene (threshold 0.001) — PM2 moderate.
• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001384479.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGT	NM_001384479.1	MANE Select	c.803C>T	p.Ala268Val	missense	Exon 2 of 5	NP_001371408.1	P01019
	AGT	NM_001382817.3		c.803C>T	p.Ala268Val	missense	Exon 2 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.803C>T	p.Ala268Val	missense	Exon 2 of 5	ENSP00000355627.5	P01019
	AGT	ENST00000680041.1		c.803C>T	p.Ala268Val	missense	Exon 2 of 5	ENSP00000504866.1	P01019
	AGT	ENST00000681269.1		c.803C>T	p.Ala268Val	missense	Exon 2 of 5	ENSP00000505985.1	P01019

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes					32
GnomAD2 exomes	0.00000796	2		251382
GnomAD4 exome	0.00000684	10	0	1461848	32
GnomAD4 genome					32

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Uncertain	-	13
AlphaMissense	Benign	-	0.066
BayesDel_addAF	Benign	T	-0.11
BayesDel_noAF	Benign	-	-0.37
CADD	Benign	-	12
DANN	Benign	-	0.83
DEOGEN2	Benign	T	0.22
Eigen	Benign	-	-1.3
Eigen_PC	Benign	-	-1.2
FATHMM_MKL	Benign	N	0.013
FuncVEP CTI	Benign	-	0.015
GPN-Star LLR	N/A	-	7.4
GPN-Star score	N/A	-	3.2
LIST_S2	Benign	T	0.46
M_CAP	Benign	D	0.029
MetaRNN	Benign	T	0.14
MetaSVM	Benign	T	-0.94
Mutation Taster	N/A	polymorphism	83/17
MutationAssessor	Benign	N	0.0
PhyloP100	Uncertain	-	4.3
popEVE	Benign	-	-2.6
PrimateAI	Benign	T	0.24
PROVEAN	Benign	N	1.7
REVEL	Benign	-	0.19
Sift	Benign	T	0.12
Sift4G	Benign	T	0.14
Varity_R	N/A	-	0.10
VESM-3B	Benign	-	-3.9

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1228544607;

hg19: chr1-230845767;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar