rs4351

Variant names:

• chr17-63492371-G-A
• rs4351
• NM_000789.4:c.2912+990G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-63492371-G-A
• chr17-63492371-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000789.4(ACE):​c.2912+990G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.498 in 152,128 control chromosomes in the GnomAD database, including 19,039 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (19039 hom., cov: 33)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.343
• Publications: 57 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.595 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.2912+990G>A		intron	N/A	NP_000780.1	P12821-1
	ACE	NM_001382700.1		c.2345+990G>A		intron	N/A	NP_001369629.1
	ACE	NM_001382701.1		c.2060+990G>A		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.2912+990G>A		intron	N/A	ENSP00000290866.4	P12821-1
	ACE	ENST00000290863.10	TSL:1	c.1190+990G>A		intron	N/A	ENSP00000290863.6	P12821-3
	ENSG00000264813	ENST00000577647.2	TSL:2	n.1190+990G>A		intron	N/A	ENSP00000464149.1	F6X3S4

Frequencies

GnomAD3 genomes AF: 0.498 AC: 75749 AN: 152010 Hom.: 19004 Cov.: 33

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.610

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.454

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.498 AC: 75826 AN: 152128 Hom.: 19039 Cov.: 33 AF XY: 0.500 AC XY: 37196 AN XY: 74368

African (AFR) AF: 0.528 AC: 21902 AN: 41486

American (AMR) AF: 0.534 AC: 8173 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1279 AN: 3472

East Asian (EAS) AF: 0.610 AC: 3161 AN: 5178

South Asian (SAS) AF: 0.614 AC: 2961 AN: 4826

European-Finnish (FIN) AF: 0.447 AC: 4729 AN: 10582

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.473 AC: 32149 AN: 67976

Other (OTH) AF: 0.460 AC: 972 AN: 2112

Alfa AF: 0.491 Hom.: 29986

Bravo AF: 0.500

Asia WGS AF: 0.640 AC: 2225 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.8
DANN	Benign	0.64
PhyloP100		0.34
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: rs4351; hg19: chr17-61569732;