1-230710048-A-T

Variant names:

Variant summary

Our verdict is The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_001384479.1(AGT):c.776T>A (p.Met259Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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.M259T: Benign (ClinVar VariationId 18068, 2 stars)

Frequency

Genomes: not found (cov: 33)

Consequence

AGT
NM_001384479.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.514

Publications

0 publications found

Variant links:

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

AGT links:

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new If you want to explore the variant's impact on the transcript NM_001384479.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 points.

PM2

Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (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 (Moderate).

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.776T>A	p.Met259Lys	missense	Exon 2 of 5	NP_001371408.1	P01019
	AGT	NM_001382817.3		c.776T>A	p.Met259Lys	missense	Exon 2 of 5	NP_001369746.2	P01019

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AGT	ENST00000366667.6	TSL:1 MANE Select	c.776T>A	p.Met259Lys	missense	Exon 2 of 5	ENSP00000355627.5	P01019
AGT	ENST00000680041.1		c.776T>A	p.Met259Lys	missense	Exon 2 of 5	ENSP00000504866.1	P01019
AGT	ENST00000681269.1		c.776T>A	p.Met259Lys	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 3 sources Large-scale international reference populations
GnomAD3 genomes					33
GnomAD4 exome					65
GnomAD4 genome					33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Benign	-	5.4
AlphaMissense	Benign	-	0.065
BayesDel_addAF	Benign	T	-0.13
BayesDel_noAF	Benign	-	-0.42
CADD	Benign	-	7.8
DANN	Benign	-	0.56
DEOGEN2	Benign	T	0.21
Eigen	Benign	-	-1.6
Eigen_PC	Benign	-	-1.5
FATHMM_MKL	Benign	N	0.056
FuncVEP CTI	Benign	-	0.0085
GPN-Star LLR	N/A	-	0.60
GPN-Star score	N/A	-	-0.60
LIST_S2	Benign	T	0.16
M_CAP	Benign	D	0.062
MetaRNN	Benign	T	0.060
MetaSVM	Benign	T	-0.87
Mutation Taster	N/A	polymorphism	94/6
MutationAssessor	Benign	N	-0.55
PhyloP100	Benign	-	0.51
popEVE	Benign	-	-2.7
PrimateAI	Benign	T	0.27
PROVEAN	Benign	N	0.81
REVEL	Benign	-	0.14
Sift	Benign	T	0.64
Sift4G	Benign	T	0.32
Varity_R	N/A	-	0.28
VESM-3B	Benign	-	-3.1

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

Publications

Other links and lift over