chr3-148740989-G-A

Variant names:

• chr3-148740989-G-A
• NM_000685.5:c.-47G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000685.5(AGTR1):​c.-47G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGTR1 NM_000685.5 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.07967
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.445
• Publications: 0 publications found

Genes affected

AGTR1 (HGNC:336): (angiotensin II receptor type 1) Angiotensin II is a potent vasopressor hormone and a primary regulator of aldosterone secretion. It is an important effector controlling blood pressure and volume in the cardiovascular system. It acts through at least two types of receptors. This gene encodes the type 1 receptor which is thought to mediate the major cardiovascular effects of angiotensin II. This gene may play a role in the generation of reperfusion arrhythmias following restoration of blood flow to ischemic or infarcted myocardium. It was previously thought that a related gene, denoted as AGTR1B, existed; however, it is now believed that there is only one type 1 receptor gene in humans. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2020]

AGTR1 Gene-Disease associations (from GenCC):

• renal tubular dysgenesis of genetic origin

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• essential hypertension, genetic

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23807955).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000685.5. 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
	AGTR1	NM_000685.5	MANE Select	c.-47G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	NP_000676.1	P30556
	AGTR1	NM_000685.5	MANE Select	c.-47G>A		splice_region	Exon 3 of 3	NP_000676.1	P30556
	AGTR1	NM_000685.5	MANE Select	c.-47G>A		5_prime_UTR	Exon 3 of 3	NP_000676.1	P30556

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTR1	ENST00000349243.8	TSL:1 MANE Select	c.-47G>A		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	ENSP00000273430.3	P30556
	AGTR1	ENST00000404754.2	TSL:1	c.-47G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	ENSP00000385612.2	P30556
	AGTR1	ENST00000497524.5	TSL:1	c.-47G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 2	ENSP00000419422.1	P30556

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Renal tubular dysgenesis of genetic origin;CN305331:Essential hypertension, genetic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.0056	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	14
DANN	Benign	0.62
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.24	T
PhyloP100		0.45
PrimateAI	Benign	0.30	T
Vest4		0.18
MVP		0.78
GERP RS		3.5
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.080
dbscSNV1_RF	Benign	0.29
SpliceAI score (max)		0.010		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

hg19: chr3-148458776; COSMIC: COSV62557738;