rs4291

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-63476833-T-A
• chr17-63476833-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.-262T>A		upstream_gene_variant		ENST00000290866.10	NP_000780.1
ACE	NM_001382700.1	c.-497T>A		upstream_gene_variant			NP_001369629.1
ACE	NM_001382701.1	c.-876T>A		upstream_gene_variant			NP_001369630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.-262T>A		upstream_gene_variant		1	NM_000789.4	ENSP00000290866.4

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

Gnomad4 AFR AF: 0.654

Gnomad4 AMR AF: 0.678

Gnomad4 ASJ AF: 0.557

Gnomad4 EAS AF: 0.639

Gnomad4 SAS AF: 0.626

Gnomad4 FIN AF: 0.616

Gnomad4 NFE AF: 0.620

Gnomad4 OTH AF: 0.619

Alfa AF: 0.621 Hom.: 3451

Bravo AF: 0.637

Asia WGS AF: 0.642 AC: 2220 AN: 3458

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.8
DANN	Benign	0.82

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4291; hg19: chr17-61554194;