rs4342

Variant names:

• chr17-63488637-A-C
• rs4342
• NM_000789.4:c.2306-11A>C

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.2306-11A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.48 in 1,456,736 control chromosomes in the GnomAD database, including 170,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (14514 hom., cov: 25)
  • Exomes 𝑓: 0.48 (170558 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACE NM_000789.4 intron
• Scores: Splicing: ADA: 0.00004375
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.517
• Publications: 23 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

ENSG00000264813 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 17-63488637-A-C is Benign according to our data. Variant chr17-63488637-A-C is described in ClinVar as Benign. ClinVar VariationId is 256801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.642 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.2306-11A>C		intron	N/A	NP_000780.1	P12821-1
	ACE	NM_001382700.1		c.1739-11A>C		intron	N/A	NP_001369629.1
	ACE	NM_001382701.1		c.1454-11A>C		intron	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.2306-11A>C		intron	N/A	ENSP00000290866.4	P12821-1
	ACE	ENST00000290863.10	TSL:1	c.584-11A>C		intron	N/A	ENSP00000290863.6	P12821-3
	ENSG00000264813	ENST00000577647.2	TSL:2	n.584-11A>C		intron	N/A	ENSP00000464149.1	F6X3S4

Frequencies

GnomAD3 genomes AF: 0.446 AC: 63346 AN: 142168 Hom.: 14490 Cov.: 25

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.644

Gnomad SAS AF: 0.568

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.309

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.408

GnomAD2 exomes AF: 0.501 AC: 125876 AN: 251102 AF XY: 0.500

Gnomad AFR exome AF: 0.413

Gnomad AMR exome AF: 0.582

Gnomad ASJ exome AF: 0.364

Gnomad EAS exome AF: 0.668

Gnomad FIN exome AF: 0.442

Gnomad NFE exome AF: 0.465

Gnomad OTH exome AF: 0.473

GnomAD4 exome AF: 0.480 AC: 699526 AN: 1456736 Hom.: 170558 Cov.: 41 AF XY: 0.481 AC XY: 348995 AN XY: 724934

African (AFR) AF: 0.409 AC: 13652 AN: 33412

American (AMR) AF: 0.575 AC: 25687 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 9502 AN: 26100

East Asian (EAS) AF: 0.649 AC: 25720 AN: 39650

South Asian (SAS) AF: 0.580 AC: 49970 AN: 86134

European-Finnish (FIN) AF: 0.444 AC: 23603 AN: 53164

Middle Eastern (MID) AF: 0.362 AC: 2086 AN: 5756

European-Non Finnish (NFE) AF: 0.470 AC: 520859 AN: 1107592

Other (OTH) AF: 0.472 AC: 28447 AN: 60226

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.446 AC: 63402 AN: 142276 Hom.: 14514 Cov.: 25 AF XY: 0.445 AC XY: 30711 AN XY: 69082

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.392 AC: 15098 AN: 38476

American (AMR) AF: 0.497 AC: 6937 AN: 13970

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1211 AN: 3370

East Asian (EAS) AF: 0.645 AC: 2987 AN: 4632

South Asian (SAS) AF: 0.569 AC: 2448 AN: 4302

European-Finnish (FIN) AF: 0.415 AC: 3964 AN: 9554

Middle Eastern (MID) AF: 0.305 AC: 86 AN: 282

European-Non Finnish (NFE) AF: 0.455 AC: 29496 AN: 64812

Other (OTH) AF: 0.415 AC: 839 AN: 2020

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.441 Hom.: 4297

Bravo AF: 0.462

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Renal tubular dysgenesis (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.1
DANN	Benign	0.54
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.0
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: rs4342; hg19: chr17-61565998;