rs753509328

Variant names:

• chrX-15517947-C-T
• rs753509328
• NM_203281.3:c.464C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_203281.3(BMX):​c.464C>T​(p.Ala155Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000732 in 1,092,310 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000073 (0 hom. 6 hem.)
• Consequence: BMX NM_203281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.436
• Publications: 0 publications found

Genes affected

BMX (HGNC:1079): (BMX non-receptor tyrosine kinase) This gene encodes a non-receptor tyrosine kinase belonging to the Tec kinase family. The protein contains a PH-like domain, which mediates membrane targeting by binding to phosphatidylinositol 3,4,5-triphosphate (PIP3), and a SH2 domain that binds to tyrosine-phosphorylated proteins and functions in signal transduction. The protein is implicated in several signal transduction pathways including the Stat pathway, and regulates differentiation and tumorigenicity of several types of cancer cells. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2016]

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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1399386).
• BS2: High Hemizygotes in GnomAdExome4 at 6 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203281.3. 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
	BMX	NM_203281.3	MANE Select	c.464C>T	p.Ala155Val	missense	Exon 6 of 19	NP_975010.1	P51813
	BMX	NM_001721.7		c.464C>T	p.Ala155Val	missense	Exon 6 of 19	NP_001712.1	P51813
	BMX	NM_001320866.2		c.464C>T	p.Ala155Val	missense	Exon 6 of 19	NP_001307795.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMX	ENST00000348343.11	TSL:1 MANE Select	c.464C>T	p.Ala155Val	missense	Exon 6 of 19	ENSP00000308774.6	P51813
	BMX	ENST00000342014.6	TSL:1	c.464C>T	p.Ala155Val	missense	Exon 6 of 19	ENSP00000340082.6	P51813
	BMX	ENST00000357607.6	TSL:2	c.464C>T	p.Ala155Val	missense	Exon 6 of 19	ENSP00000350224.2	P51813

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000169 AC: 3 AN: 177484 AF XY: 0.0000320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000374

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000732 AC: 8 AN: 1092310 Hom.: 0 Cov.: 27 AF XY: 0.0000167 AC XY: 6 AN XY: 358460

African (AFR) AF: 0.00 AC: 0 AN: 26190

American (AMR) AF: 0.00 AC: 0 AN: 34626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19259

East Asian (EAS) AF: 0.00 AC: 0 AN: 30104

South Asian (SAS) AF: 0.00 AC: 0 AN: 53458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4101

European-Non Finnish (NFE) AF: 0.00000835 AC: 7 AN: 838383

Other (OTH) AF: 0.0000218 AC: 1 AN: 45889

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000121

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.44
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.094
Sift	Benign	0.18	T
Sift4G	Benign	0.34	T
Polyphen		0.0010	B
Vest4		0.079
MutPred		0.29		Loss of disorder (P = 0.1031)
MVP		0.55
MPC		0.34
ClinPred		0.051	T
GERP RS		4.1
Varity_R		0.098
gMVP		0.32
Mutation Taster		=100/0	polymorphism

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: rs753509328; hg19: chrX-15536070;