17-63477096-T-C

Variant names:

• chr17-63477096-T-C
• rs1005792910
• NM_000789.4:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000789.4(ACE):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000026 in 1,155,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: ACE NM_000789.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.25
• Publications: 4 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 14 pathogenic variants. Next in-frame start position is after 147 codons. Genomic position: 63479028. Lost 0.112 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-63477096-T-C is Pathogenic according to our data. Variant chr17-63477096-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1215324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2T>C	p.Met1?	start_lost	Exon 1 of 25	NP_000780.1	P12821-1
	ACE	NM_001382700.1		c.-234T>C		5_prime_UTR	Exon 1 of 22	NP_001369629.1
	ACE	NM_001382701.1		c.-613T>C		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.2T>C	p.Met1?	start_lost	Exon 1 of 25	ENSP00000290866.4	P12821-1
	ACE	ENST00000953328.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 25	ENSP00000623387.1
	ACE	ENST00000884279.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 25	ENSP00000554338.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000260 AC: 3 AN: 1155418 Hom.: 0 Cov.: 29 AF XY: 0.00000357 AC XY: 2 AN XY: 560336

African (AFR) AF: 0.00 AC: 0 AN: 22620

American (AMR) AF: 0.00 AC: 0 AN: 8234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14622

East Asian (EAS) AF: 0.0000389 AC: 1 AN: 25716

South Asian (SAS) AF: 0.0000249 AC: 1 AN: 40234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3114

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 967620

Other (OTH) AF: 0.00 AC: 0 AN: 46728

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Renal tubular dysgenesis of genetic origin (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-1.0	T
PhyloP100		1.3
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.054	T
Polyphen		0.072	B
Vest4		0.67
MutPred		0.99		Gain of glycosylation at M1 (P = 0.0088)
MVP		0.70
ClinPred		0.99	D
GERP RS		3.3
PromoterAI		0.052	Neutral
Varity_R		0.93
gMVP		0.48
Mutation Taster		=19/181	disease causing

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: rs1005792910; hg19: chr17-61554457;