rs4311

Positions:

• chr17-63483402-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000789.4(ACE):​c.1488-58T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.55 in 1,530,568 control chromosomes in the GnomAD database, including 235,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (28094 hom., cov: 31)
  • Exomes 𝑓: 0.54 (207200 hom.)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0140

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-63483402-T-C is Benign according to our data. Variant chr17-63483402-T-C is described in ClinVar as [Benign]. Clinvar id is 1263928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACE	NM_000789.4	c.1488-58T>C		intron_variant		ENST00000290866.10	NP_000780.1
ACE	NM_001382700.1	c.921-58T>C		intron_variant			NP_001369629.1
ACE	NM_001382701.1	c.636-58T>C		intron_variant			NP_001369630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.1488-58T>C		intron_variant		1	NM_000789.4	ENSP00000290866.4
ACE	ENST00000428043.5	c.1488-58T>C		intron_variant		2		ENSP00000397593.2
ACE	ENST00000582678.5	n.*887-58T>C		intron_variant		2		ENSP00000462995.1
ACE	ENST00000584529.5	n.1377-58T>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.600 AC: 91078 AN: 151870 Hom.: 28035 Cov.: 31

Gnomad AFR AF: 0.751

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.417

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.547

GnomAD4 exome AF: 0.545 AC: 750923 AN: 1378580 Hom.: 207200 Cov.: 23 AF XY: 0.545 AC XY: 376323 AN XY: 690722

Gnomad4 AFR exome AF: 0.755

Gnomad4 AMR exome AF: 0.622

Gnomad4 ASJ exome AF: 0.435

Gnomad4 EAS exome AF: 0.652

Gnomad4 SAS exome AF: 0.640

Gnomad4 FIN exome AF: 0.535

Gnomad4 NFE exome AF: 0.527

Gnomad4 OTH exome AF: 0.550

GnomAD4 genome AF: 0.600 AC: 91201 AN: 151988 Hom.: 28094 Cov.: 31 AF XY: 0.601 AC XY: 44656 AN XY: 74262

Gnomad4 AFR AF: 0.751

Gnomad4 AMR AF: 0.592

Gnomad4 ASJ AF: 0.446

Gnomad4 EAS AF: 0.663

Gnomad4 SAS AF: 0.650

Gnomad4 FIN AF: 0.535

Gnomad4 NFE AF: 0.523

Gnomad4 OTH AF: 0.551

Alfa AF: 0.529 Hom.: 28960

Bravo AF: 0.608

Asia WGS AF: 0.692 AC: 2404 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	13
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs4311; hg19: chr17-61560763;