rs4364

Variant names:

• chr17-63497301-C-A
• rs4364
• NM_000789.4:c.3856C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-63497301-C-A
• chr17-63497301-C-G
• chr17-63497301-C-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.3856C>A​(p.Arg1286Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00634 in 1,550,850 control chromosomes in the GnomAD database, including 526 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1286H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.034 (274 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (252 hom.)
• Consequence: ACE NM_000789.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.16
• Publications: 15 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

ENSG00000264813 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018135011).
• BP6: Variant 17-63497301-C-A is Benign according to our data. Variant chr17-63497301-C-A is described in ClinVar as Benign. ClinVar VariationId is 256808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 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.3856C>A	p.Arg1286Ser	missense	Exon 25 of 25	NP_000780.1
	ACE	NM_001382700.1		c.3289C>A	p.Arg1097Ser	missense	Exon 22 of 22	NP_001369629.1
	ACE	NM_001382701.1		c.3004C>A	p.Arg1002Ser	missense	Exon 23 of 23	NP_001369630.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACE	ENST00000290866.10	TSL:1 MANE Select	c.3856C>A	p.Arg1286Ser	missense	Exon 25 of 25	ENSP00000290866.4
	ACE	ENST00000290863.10	TSL:1	c.2134C>A	p.Arg712Ser	missense	Exon 14 of 14	ENSP00000290863.6
	ENSG00000264813	ENST00000577647.2	TSL:2	n.1969+316C>A		intron	N/A	ENSP00000464149.1

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5125 AN: 152164 Hom.: 272 Cov.: 33

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.00733 AC: 1082 AN: 147546 AF XY: 0.00538

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.00547

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000275

Gnomad OTH exome AF: 0.00284

GnomAD4 exome AF: 0.00336 AC: 4704 AN: 1398568 Hom.: 252 Cov.: 34 AF XY: 0.00292 AC XY: 2016 AN XY: 690298

African (AFR) AF: 0.120 AC: 3819 AN: 31806

American (AMR) AF: 0.00682 AC: 245 AN: 35940

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 36084

South Asian (SAS) AF: 0.000377 AC: 30 AN: 79480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46794

Middle Eastern (MID) AF: 0.00428 AC: 20 AN: 4670

European-Non Finnish (NFE) AF: 0.000137 AC: 148 AN: 1080652

Other (OTH) AF: 0.00762 AC: 442 AN: 57972

GnomAD4 genome AF: 0.0337 AC: 5133 AN: 152282 Hom.: 274 Cov.: 33 AF XY: 0.0324 AC XY: 2415 AN XY: 74458

African (AFR) AF: 0.117 AC: 4848 AN: 41542

American (AMR) AF: 0.0128 AC: 196 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68012

Other (OTH) AF: 0.0251 AC: 53 AN: 2114

Alfa AF: 0.00443 Hom.: 51

Bravo AF: 0.0394

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0850 AC: 349

ESP6500EA AF: 0.000492 AC: 4

ExAC AF: 0.00597 AC: 633

Asia WGS AF: 0.00404 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N
PhyloP100		1.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.046
Sift	Benign	0.28	T
Sift4G	Benign	0.25	T
Polyphen		0.020	B
Vest4		0.15
MVP		0.58
MPC		0.12
ClinPred		0.0060	T
GERP RS		3.8
Varity_R		0.13
gMVP		0.40
Mutation Taster		=93/7	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: rs4364; hg19: chr17-61574662;