rs4344

Variant names:

• chr17-63489363-G-A
• rs4344
• NM_000789.4:c.2641+231G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-63489363-G-A
• chr17-63489363-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000789.4(ACE):​c.2641+231G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 152,042 control chromosomes in the GnomAD database, including 16,463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.46 (16463 hom., cov: 32)
• Consequence: ACE NM_000789.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.187
• Publications: 40 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-63489363-G-A is Benign according to our data. Variant chr17-63489363-G-A is described in ClinVar as [Benign]. Clinvar id is 1226144.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.2641+231G>A		intron_variant	Intron 17 of 24	ENST00000290866.10	NP_000780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE	ENST00000290866.10	c.2641+231G>A		intron_variant	Intron 17 of 24	1	NM_000789.4	ENSP00000290866.4
ENSG00000264813	ENST00000577647.2	n.919+231G>A		intron_variant	Intron 6 of 30	2		ENSP00000464149.1

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70098 AN: 151924 Hom.: 16433 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.520

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.420

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

GnomAD4 genome AF: 0.461 AC: 70166 AN: 152042 Hom.: 16463 Cov.: 32 AF XY: 0.464 AC XY: 34507 AN XY: 74328

African (AFR) AF: 0.407 AC: 16872 AN: 41456

American (AMR) AF: 0.521 AC: 7962 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1275 AN: 3470

East Asian (EAS) AF: 0.663 AC: 3420 AN: 5156

South Asian (SAS) AF: 0.595 AC: 2871 AN: 4824

European-Finnish (FIN) AF: 0.447 AC: 4738 AN: 10588

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31653 AN: 67954

Other (OTH) AF: 0.427 AC: 900 AN: 2110

Alfa AF: 0.451 Hom.: 24576

Bravo AF: 0.459

Asia WGS AF: 0.635 AC: 2209 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.1
DANN	Benign	0.51
PhyloP100		0.19
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: rs4344; hg19: chr17-61566724;