chr17-63484948-C-T

Variant names:

• chr17-63484948-C-T
• rs4316
• ENST00000290863.10:c.81C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000290863.10(ACE):​c.81C>T​(p.Pro27Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,597,562 control chromosomes in the GnomAD database, including 182,094 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (16062 hom., cov: 33)
  • Exomes 𝑓: 0.48 (166032 hom.)
• Consequence: ACE ENST00000290863.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.17
• Publications: 45 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-63484948-C-T is Benign according to our data. Variant chr17-63484948-C-T is described in ClinVar as Benign. ClinVar VariationId is 1188854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE	NM_000789.4	c.1922-288C>T		intron_variant	Intron 12 of 24	ENST00000290866.10	NP_000780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000264813	ENST00000577647.2	n.81C>T		non_coding_transcript_exon_variant	Exon 1 of 31	2		ENSP00000464149.1
ACE	ENST00000290866.10	c.1922-288C>T		intron_variant	Intron 12 of 24	1	NM_000789.4	ENSP00000290866.4

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69126 AN: 152002 Hom.: 16033 Cov.: 33

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.665

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.414

GnomAD2 exomes AF: 0.495 AC: 110462 AN: 223204 AF XY: 0.495

Gnomad AFR exome AF: 0.381

Gnomad AMR exome AF: 0.573

Gnomad ASJ exome AF: 0.371

Gnomad EAS exome AF: 0.666

Gnomad FIN exome AF: 0.444

Gnomad NFE exome AF: 0.458

Gnomad OTH exome AF: 0.468

GnomAD4 exome AF: 0.477 AC: 688874 AN: 1445442 Hom.: 166032 Cov.: 74 AF XY: 0.478 AC XY: 342895 AN XY: 717496

African (AFR) AF: 0.380 AC: 12592 AN: 33166

American (AMR) AF: 0.566 AC: 23615 AN: 41746

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 9603 AN: 25854

East Asian (EAS) AF: 0.649 AC: 25264 AN: 38956

South Asian (SAS) AF: 0.578 AC: 48360 AN: 83700

European-Finnish (FIN) AF: 0.447 AC: 23336 AN: 52238

Middle Eastern (MID) AF: 0.364 AC: 2093 AN: 5746

European-Non Finnish (NFE) AF: 0.467 AC: 516033 AN: 1104196

Other (OTH) AF: 0.468 AC: 27978 AN: 59840

GnomAD4 genome AF: 0.455 AC: 69190 AN: 152120 Hom.: 16062 Cov.: 33 AF XY: 0.458 AC XY: 34070 AN XY: 74374

African (AFR) AF: 0.389 AC: 16133 AN: 41486

American (AMR) AF: 0.517 AC: 7911 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1303 AN: 3470

East Asian (EAS) AF: 0.666 AC: 3427 AN: 5148

South Asian (SAS) AF: 0.594 AC: 2866 AN: 4824

European-Finnish (FIN) AF: 0.448 AC: 4754 AN: 10608

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.462 AC: 31438 AN: 67980

Other (OTH) AF: 0.421 AC: 886 AN: 2106

Alfa AF: 0.453 Hom.: 11676

Bravo AF: 0.452

Asia WGS AF: 0.635 AC: 2206 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Renal tubular dysgenesis Benign:1

Jul 14, 2021

Genome-Nilou Lab

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	-0.81
CADD	Benign	6.3
DANN	Benign	0.54
PhyloP100		-1.2
PromoterAI		0.00040	Neutral
Mutation Taster		=289/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs4316; hg19: chr17-61562309; COSMIC: COSV52007399; COSMIC: COSV52007399;