Genetic Variant NM_001371415.1:c.439+4G>A (chrX-15592225-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001371415.1(ACE2):c.439+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 1,171,182 control chromosomes in the GnomAD database, including 22,621 homozygotes. There are 83,425 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.24 ( 2470 hom., 8043 hem., cov: 23)

Exomes 𝑓: 0.22 ( 20151 hom. 75382 hem. )

Consequence

ACE2
NM_001371415.1 splice_region, intron

Scores

Splicing: ADA: 0.001385

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.09

Variant links:

Genes affected

ACE2 (HGNC:13557): (angiotensin converting enzyme 2) The protein encoded by this gene belongs to the angiotensin-converting enzyme family of dipeptidyl carboxydipeptidases and has considerable homology to human angiotensin 1 converting enzyme. This secreted protein catalyzes the cleavage of angiotensin I into angiotensin 1-9, and angiotensin II into the vasodilator angiotensin 1-7. ACE2 is known to be expressed in various human organs, and its organ- and cell-specific expression suggests that it may play a role in the regulation of cardiovascular and renal function, as well as fertility. In addition, the encoded protein is a functional receptor for the spike glycoprotein of the human coronavirus HCoV-NL63 and the human severe acute respiratory syndrome coronaviruses, SARS-CoV and SARS-CoV-2, the latter is the causative agent of coronavirus disease-2019 (COVID-19). Multiple splice variants have been found for this gene and the dACE2 (or MIRb-ACE2) splice variant has been found to be interferon inducible. [provided by RefSeq, Nov 2020]

ACE2 links:

ENSG00000285602 (HGNC:):

ENSG00000285602 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACE2	NM_001371415.1 link	c.439+4G>A		splice_region_variant, intron_variant	Intron 3 of 17	ENST00000252519.8	NP_001358344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACE2	ENST00000252519.8 link	c.439+4G>A		splice_region_variant, intron_variant	Intron 3 of 17	1	NM_001371415.1	ENSP00000252519.3		Q9BYF1-1
ENSG00000285602	ENST00000649243.1 link	n.*517+4G>A		splice_region_variant, intron_variant	Intron 8 of 19			ENSP00000497489.1		A0A3B3IT09

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

26503

AN:

111103

Hom.:

2470

Cov.:

AF XY:

0.241

AC XY:

8029

AN XY:

33373

show subpopulations

Gnomad AFR

AF:

0.220

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.367

Gnomad ASJ

AF:

0.260

Gnomad EAS

AF:

0.527

Gnomad SAS

AF:

0.443

Gnomad FIN

AF:

0.188

Gnomad MID

AF:

0.211

Gnomad NFE

AF:

0.200

Gnomad OTH

AF:

0.235

GnomAD3 exomes

AF:

0.280

AC:

45478

AN:

162393

Hom.:

5212

AF XY:

0.274

AC XY:

14414

AN XY:

52599

show subpopulations

Gnomad AFR exome

AF:

0.221

Gnomad AMR exome

AF:

0.394

Gnomad ASJ exome

AF:

0.258

Gnomad EAS exome

AF:

0.547

Gnomad SAS exome

AF:

0.453

Gnomad FIN exome

AF:

0.191

Gnomad NFE exome

AF:

0.200

Gnomad OTH exome

AF:

0.254

GnomAD4 exome

AF:

0.222

AC:

234903

AN:

1060028

Hom.:

20151

Cov.:

AF XY:

0.224

AC XY:

75382

AN XY:

336352

show subpopulations

Gnomad4 AFR exome

AF:

0.219

Gnomad4 AMR exome

AF:

0.390

Gnomad4 ASJ exome

AF:

0.256

Gnomad4 EAS exome

AF:

0.521

Gnomad4 SAS exome

AF:

0.440

Gnomad4 FIN exome

AF:

0.191

Gnomad4 NFE exome

AF:

0.191

Gnomad4 OTH exome

AF:

0.242

GnomAD4 genome

AF:

0.239

AC:

26517

AN:

111154

Hom.:

2470

Cov.:

AF XY:

0.241

AC XY:

8043

AN XY:

33434

show subpopulations

Gnomad4 AFR

AF:

0.220

Gnomad4 AMR

AF:

0.368

Gnomad4 ASJ

AF:

0.260

Gnomad4 EAS

AF:

0.526

Gnomad4 SAS

AF:

0.443

Gnomad4 FIN

AF:

0.188

Gnomad4 NFE

AF:

0.200

Gnomad4 OTH

AF:

0.237

Alfa

AF:

0.216

Hom.:

8163

Bravo

AF:

0.254

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

3.0

DANN

Benign

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0014

dbscSNV1_RF

Benign

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over