rs4295

Variant names:

• chr17-63478937-C-G
• rs4295
• NM_000789.4:c.418-70C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000789.4(ACE):​c.418-70C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.623 in 1,362,354 control chromosomes in the GnomAD database, including 265,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (28807 hom., cov: 31)
  • Exomes 𝑓: 0.62 (236312 hom.)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.498
• Publications: 50 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 of genetic origin

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

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-63478937-C-G is Benign according to our data. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-63478937-C-G is described in CliVar as Benign. Clinvar id is 1273999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.418-70C>G		intron_variant	Intron 2 of 24	ENST00000290866.10	NP_000780.1
ACE	NM_001382700.1	c.182+839C>G		intron_variant	Intron 2 of 21		NP_001369629.1
ACE	NM_001382701.1	c.-198+839C>G		intron_variant	Intron 2 of 22		NP_001369630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.418-70C>G		intron_variant	Intron 2 of 24	1	NM_000789.4	ENSP00000290866.4

Frequencies

GnomAD3 genomes AF: 0.615 AC: 93385 AN: 151798 Hom.: 28773 Cov.: 31

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.615

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.605

GnomAD4 exome AF: 0.624 AC: 755668 AN: 1210438 Hom.: 236312 Cov.: 17 AF XY: 0.623 AC XY: 379444 AN XY: 609270

African (AFR) AF: 0.583 AC: 16194 AN: 27754

American (AMR) AF: 0.706 AC: 27382 AN: 38778

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 13073 AN: 24086

East Asian (EAS) AF: 0.637 AC: 22668 AN: 35600

South Asian (SAS) AF: 0.626 AC: 48013 AN: 76706

European-Finnish (FIN) AF: 0.620 AC: 30029 AN: 48422

Middle Eastern (MID) AF: 0.577 AC: 3067 AN: 5320

European-Non Finnish (NFE) AF: 0.624 AC: 562926 AN: 901658

Other (OTH) AF: 0.620 AC: 32316 AN: 52114

GnomAD4 genome AF: 0.615 AC: 93469 AN: 151916 Hom.: 28807 Cov.: 31 AF XY: 0.616 AC XY: 45739 AN XY: 74240

African (AFR) AF: 0.590 AC: 24449 AN: 41434

American (AMR) AF: 0.667 AC: 10186 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 1921 AN: 3464

East Asian (EAS) AF: 0.646 AC: 3323 AN: 5146

South Asian (SAS) AF: 0.627 AC: 3004 AN: 4792

European-Finnish (FIN) AF: 0.615 AC: 6493 AN: 10556

Middle Eastern (MID) AF: 0.531 AC: 156 AN: 294

European-Non Finnish (NFE) AF: 0.620 AC: 42148 AN: 67930

Other (OTH) AF: 0.600 AC: 1266 AN: 2110

Alfa AF: 0.617 Hom.: 3596

Bravo AF: 0.615

Asia WGS AF: 0.643 AC: 2235 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.7
DANN	Benign	0.39
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

dbSNP: rs4295; hg19: chr17-61556298;