17-63476833-T-A

Variant names:

• chr17-63476833-T-A
• rs4291
• NM_000789.4:c.-262T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000789.4(ACE):​c.-262T>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 151,724 control chromosomes in the GnomAD database, including 30,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.63 (30526 hom., cov: 31)
• Consequence: ACE NM_000789.4 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.99
• Publications: 170 publications found

Genes affected

ACE (HGNC:2707): (angiotensin I converting enzyme) This gene encodes an enzyme involved in blood pressure regulation and electrolyte balance. It catalyzes the conversion of angiotensin I into a physiologically active peptide angiotensin II. Angiotensin II is a potent vasopressor and aldosterone-stimulating peptide that controls blood pressure and fluid-electrolyte balance. This angiotensin converting enzyme (ACE) also inactivates the vasodilator protein, bradykinin. Accordingly, the encoded enzyme increases blood pressure and is a drug target of ACE inhibitors, which are often prescribed to reduce blood pressure. This enzyme additionally plays a role in fertility through its ability to cleave and release GPI-anchored membrane proteins in spermatozoa. Many studies have associated the presence or absence of a 287 bp Alu repeat element in this gene with the levels of circulating enzyme. This polymorphism, as well as mutations in this gene, have been implicated in a wide variety of diseases including cardiovascular pathophysiologies, psoriasis, renal disease, stroke, and Alzheimer's disease. Regulation of the homologous ACE2 gene may be involved in progression of disease caused by several human coronaviruses, including SARS-CoV and SARS-CoV-2. Alternative splicing results in multiple transcript variants encoding both somatic (sACE) and male-specific testicular (tACE) isoforms. [provided by RefSeq, Sep 2020]

ACE Gene-Disease associations (from GenCC):

• renal tubular dysgenesis - ACE

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• renal tubular dysgenesis of genetic origin

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• intracerebral hemorrhage

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-63476833-T-A is Benign according to our data. Variant chr17-63476833-T-A is described in ClinVar as Benign. ClinVar VariationId is 1231511.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.667 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000789.4. 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
	ACE	NM_000789.4	MANE Select	c.-262T>A		upstream_gene	N/A	NP_000780.1	P12821-1
	ACE	NM_001382700.1		c.-497T>A		upstream_gene	N/A	NP_001369629.1
	ACE	NM_001382701.1		c.-876T>A		upstream_gene	N/A	NP_001369630.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACE	ENST00000290866.10	TSL:1 MANE Select	c.-262T>A		upstream_gene	N/A	ENSP00000290866.4	P12821-1
	ACE	ENST00000953328.1		c.-262T>A		upstream_gene	N/A	ENSP00000623387.1
	ACE	ENST00000884279.1		c.-262T>A		upstream_gene	N/A	ENSP00000554338.1

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96109 AN: 151614 Hom.: 30493 Cov.: 31

Gnomad AFR AF: 0.654

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.640

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.616

Gnomad MID AF: 0.558

Gnomad NFE AF: 0.620

Gnomad OTH AF: 0.624

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.634 AC: 96188 AN: 151724 Hom.: 30526 Cov.: 31 AF XY: 0.634 AC XY: 47024 AN XY: 74144

African (AFR) AF: 0.654 AC: 27112 AN: 41426

American (AMR) AF: 0.678 AC: 10363 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 1931 AN: 3468

East Asian (EAS) AF: 0.639 AC: 3250 AN: 5084

South Asian (SAS) AF: 0.626 AC: 3013 AN: 4816

European-Finnish (FIN) AF: 0.616 AC: 6513 AN: 10580

Middle Eastern (MID) AF: 0.548 AC: 159 AN: 290

European-Non Finnish (NFE) AF: 0.620 AC: 42025 AN: 67766

Other (OTH) AF: 0.619 AC: 1303 AN: 2106

Alfa AF: 0.621 Hom.: 3451

Bravo AF: 0.637

Asia WGS AF: 0.642 AC: 2220 AN: 3458

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.8
DANN	Benign	0.82
PhyloP100		-2.0
PromoterAI		-0.017	Neutral

Splicing

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

Other links and lift over

dbSNP: rs4291; hg19: chr17-61554194;