rs4363

Variant names:

• chr17-63497131-G-A
• rs4363
• NM_000789.4:c.3692-6G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-63497131-G-A
• chr17-63497131-G-C
• chr17-63497131-G-T

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.3692-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 1,600,104 control chromosomes in the GnomAD database, including 195,701 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20108 hom., cov: 32)
  • Exomes 𝑓: 0.49 (175593 hom.)
• Consequence: ACE NM_000789.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001837
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.08
• Publications: 55 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=-0.84).
• BP6: Variant 17-63497131-G-A is Benign according to our data. Variant chr17-63497131-G-A is described in ClinVar as Benign. ClinVar VariationId is 256806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.598 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.3692-6G>A		splice_region intron	N/A	NP_000780.1	P12821-1
	ACE	NM_001382700.1		c.3125-6G>A		splice_region intron	N/A	NP_001369629.1
	ACE	NM_001382701.1		c.2840-6G>A		splice_region 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.3692-6G>A		splice_region intron	N/A	ENSP00000290866.4	P12821-1
	ACE	ENST00000290863.10	TSL:1	c.1970-6G>A		splice_region intron	N/A	ENSP00000290863.6	P12821-3
	ENSG00000264813	ENST00000577647.2	TSL:2	n.1969+146G>A		intron	N/A	ENSP00000464149.1	F6X3S4

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77559 AN: 151570 Hom.: 20068 Cov.: 32

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.369

Gnomad NFE AF: 0.471

Gnomad OTH AF: 0.463

GnomAD2 exomes AF: 0.521 AC: 118150 AN: 226988 AF XY: 0.517

Gnomad AFR exome AF: 0.587

Gnomad AMR exome AF: 0.594

Gnomad ASJ exome AF: 0.353

Gnomad EAS exome AF: 0.610

Gnomad FIN exome AF: 0.459

Gnomad NFE exome AF: 0.473

Gnomad OTH exome AF: 0.484

GnomAD4 exome AF: 0.490 AC: 709470 AN: 1448414 Hom.: 175593 Cov.: 50 AF XY: 0.491 AC XY: 353643 AN XY: 720536

African (AFR) AF: 0.575 AC: 19198 AN: 33396

American (AMR) AF: 0.587 AC: 25784 AN: 43920

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 9087 AN: 25932

East Asian (EAS) AF: 0.582 AC: 23019 AN: 39520

South Asian (SAS) AF: 0.606 AC: 51775 AN: 85468

European-Finnish (FIN) AF: 0.455 AC: 20723 AN: 45530

Middle Eastern (MID) AF: 0.379 AC: 1861 AN: 4910

European-Non Finnish (NFE) AF: 0.476 AC: 528722 AN: 1109694

Other (OTH) AF: 0.488 AC: 29301 AN: 60044

GnomAD4 genome AF: 0.512 AC: 77661 AN: 151690 Hom.: 20108 Cov.: 32 AF XY: 0.513 AC XY: 38011 AN XY: 74124

African (AFR) AF: 0.574 AC: 23753 AN: 41356

American (AMR) AF: 0.548 AC: 8364 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1224 AN: 3466

East Asian (EAS) AF: 0.602 AC: 3077 AN: 5110

South Asian (SAS) AF: 0.616 AC: 2966 AN: 4814

European-Finnish (FIN) AF: 0.461 AC: 4853 AN: 10536

Middle Eastern (MID) AF: 0.372 AC: 108 AN: 290

European-Non Finnish (NFE) AF: 0.471 AC: 31953 AN: 67846

Other (OTH) AF: 0.469 AC: 988 AN: 2108

Alfa AF: 0.486 Hom.: 32043

Bravo AF: 0.517

Asia WGS AF: 0.647 AC: 2250 AN: 3478

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	-0.84
CADD	Benign	2.2
DANN	Benign	0.68
PhyloP100		-1.1
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.070		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: rs4363; hg19: chr17-61574492; COSMIC: COSV52005664; COSMIC: COSV52005664;