NM_203281.3:c.425G>A

Variant names:

• chrX-15516211-G-A
• rs2147108820
• NM_203281.3:c.425G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_203281.3(BMX):​c.425G>A​(p.Gly142Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: BMX NM_203281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.57
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

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.425G>A	p.Gly142Glu	missense	Exon 5 of 19	NP_975010.1	P51813
	BMX	NM_001721.7		c.425G>A	p.Gly142Glu	missense	Exon 5 of 19	NP_001712.1	P51813
	BMX	NM_001320866.2		c.425G>A	p.Gly142Glu	missense	Exon 5 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.425G>A	p.Gly142Glu	missense	Exon 5 of 19	ENSP00000308774.6	P51813
	BMX	ENST00000342014.6	TSL:1	c.425G>A	p.Gly142Glu	missense	Exon 5 of 19	ENSP00000340082.6	P51813
	BMX	ENST00000357607.6	TSL:2	c.425G>A	p.Gly142Glu	missense	Exon 5 of 19	ENSP00000350224.2	P51813

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.89		Loss of catalytic residue at C143 (P = 0.045)
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.85
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: 20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2147108820; hg19: chrX-15534334; COSMIC: COSV59591210;