chr17-63477116-C-T

Variant names:

• chr17-63477116-C-T
• rs1333116255
• NM_000789.4:c.22C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001382700.1(ACE):​c.-214C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000749 in 1,334,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000059 (0 hom.)
• Consequence: ACE NM_001382700.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.694
• Publications: 1 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.080270916).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001382700.1. 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.22C>T	p.Arg8Trp	missense	Exon 1 of 25	NP_000780.1	P12821-1
	ACE	NM_001382700.1		c.-214C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 22	NP_001369629.1
	ACE	NM_001382701.1		c.-593C>T		5_prime_UTR_premature_start_codon_gain	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.22C>T	p.Arg8Trp	missense	Exon 1 of 25	ENSP00000290866.4	P12821-1
	ACE	ENST00000953328.1		c.22C>T	p.Arg8Trp	missense	Exon 1 of 25	ENSP00000623387.1
	ACE	ENST00000884279.1		c.22C>T	p.Arg8Trp	missense	Exon 1 of 25	ENSP00000554338.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151280 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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

GnomAD2 exomes AF: 0.0000777 AC: 1 AN: 12870 AF XY: 0.000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000856

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000591 AC: 7 AN: 1183706 Hom.: 0 Cov.: 28 AF XY: 0.0000104 AC XY: 6 AN XY: 577236

African (AFR) AF: 0.00 AC: 0 AN: 23168

American (AMR) AF: 0.000104 AC: 1 AN: 9650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15852

East Asian (EAS) AF: 0.00 AC: 0 AN: 26196

South Asian (SAS) AF: 0.00 AC: 0 AN: 46534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3278

European-Non Finnish (NFE) AF: 0.00000611 AC: 6 AN: 982672

Other (OTH) AF: 0.00 AC: 0 AN: 48098

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151280 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73872

African (AFR) AF: 0.00 AC: 0 AN: 41206

American (AMR) AF: 0.000131 AC: 2 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67760

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Microvascular complications of diabetes, susceptibility to, 3;C3281105:Hemorrhage, intracerebral, susceptibility to;C5681536:Renal tubular dysgenesis of genetic origin (1)
-	1	-	Renal tubular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.69
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.0060	B
Vest4		0.12
MutPred		0.29		Loss of methylation at R8 (P = 0.0061)
MVP		0.59
MPC		0.10
ClinPred		0.14	T
GERP RS		3.2
PromoterAI		-0.042	Neutral
Varity_R		0.053
gMVP		0.45

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: rs1333116255; hg19: chr17-61554477;