chr17-63477126-G-GGCTGCT

Variant names:

• chr17-63477126-G-GGCTGCT
• rs900084108
• NM_000789.4:c.38_43dupTGCTGC

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP3

The NM_000789.4(ACE):​c.38_43dupTGCTGC​(p.Leu13_Leu14dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000713 in 1,402,100 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P15P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: ACE NM_000789.4 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 0 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: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• intracerebral hemorrhage

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_000789.4

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.38_43dupTGCTGC	p.Leu13_Leu14dup	disruptive_inframe_insertion	Exon 1 of 25	NP_000780.1	P12821-1
	ACE	NM_001382700.1		c.-198_-193dupTGCTGC		5_prime_UTR	Exon 1 of 22	NP_001369629.1
	ACE	NM_001382701.1		c.-577_-572dupTGCTGC		5_prime_UTR	Exon 1 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.38_43dupTGCTGC	p.Leu13_Leu14dup	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000290866.4	P12821-1
	ACE	ENST00000953328.1		c.38_43dupTGCTGC	p.Leu13_Leu14dup	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000623387.1
	ACE	ENST00000884279.1		c.38_43dupTGCTGC	p.Leu13_Leu14dup	disruptive_inframe_insertion	Exon 1 of 25	ENSP00000554338.1

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151012 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000719 AC: 9 AN: 1251088 Hom.: 0 Cov.: 29 AF XY: 0.00000977 AC XY: 6 AN XY: 613924

African (AFR) AF: 0.00 AC: 0 AN: 25256

American (AMR) AF: 0.00 AC: 0 AN: 21916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20172

East Asian (EAS) AF: 0.00 AC: 0 AN: 26604

South Asian (SAS) AF: 0.00 AC: 0 AN: 59832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3606

European-Non Finnish (NFE) AF: 0.00000791 AC: 8 AN: 1011284

Other (OTH) AF: 0.0000196 AC: 1 AN: 51054

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151012 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73742

African (AFR) AF: 0.00 AC: 0 AN: 41054

American (AMR) AF: 0.00 AC: 0 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67724

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=87/13	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs900084108; hg19: chr17-61554487;