17-63477096-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_000789.4 (ACE) was described as [Likely_pathogenic] in ClinVar as 2585611
• 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 [Likely_pathogenic]. Clinvar id is 1215324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACE	NM_000789.4	c.2T>C	p.Met1?	start_lost	1/25	ENST00000290866.10
ACE	NM_001382700.1	c.-234T>C		5_prime_UTR_variant	1/22
ACE	NM_001382701.1	c.-613T>C		5_prime_UTR_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACE	ENST00000290866.10	c.2T>C	p.Met1?	start_lost	1/25	1	NM_000789.4	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000389

Gnomad4 SAS exome AF: 0.0000249

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000103

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2021

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge -

Renal tubular dysgenesis of genetic origin Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

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Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-0.29	N;N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.054	T;T
Polyphen		0.072	.;B
Vest4		0.67
MutPred		0.99		Gain of glycosylation at M1 (P = 0.0088);Gain of glycosylation at M1 (P = 0.0088);
MVP		0.70
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.93
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs1005792910; hg19: chr17-61554457;