X-15517955-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_203281.3(BMX):c.472G>A(p.Glu158Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,206,033 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000091 (0 hom. 6 hem.)
• Consequence: BMX NM_203281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13248917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMX	NM_203281.3	c.472G>A	p.Glu158Lys	missense_variant	6/19	ENST00000348343.11
BMX	NM_001721.7	c.472G>A	p.Glu158Lys	missense_variant	6/19
BMX	NM_001320866.2	c.472G>A	p.Glu158Lys	missense_variant	6/19
BMX	XM_017029752.3	c.472G>A	p.Glu158Lys	missense_variant	6/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMX	ENST00000348343.11	c.472G>A	p.Glu158Lys	missense_variant	6/19	1	NM_203281.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112366 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34540

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.000661

GnomAD4 exome AF: 0.00000914 AC: 10 AN: 1093667 Hom.: 0 Cov.: 27 AF XY: 0.0000167 AC XY: 6 AN XY: 359743

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112366 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34540

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000375

Gnomad4 OTH AF: 0.000661

Bravo AF: 0.00000756

EpiCase AF: 0.000111

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.472G>A (p.E158K) alteration is located in exon 6 (coding exon 5) of the BMX gene. This alteration results from a G to A substitution at nucleotide position 472, causing the glutamic acid (E) at amino acid position 158 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	19
Dann	Benign	0.45
DEOGEN2	Benign	0.10	T;T;T
FATHMM_MKL	Benign	0.55	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.18	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.91	T;T;T
Sift4G	Benign	0.91	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.16
MutPred		0.52		Gain of methylation at E158 (P = 0.0095);Gain of methylation at E158 (P = 0.0095);Gain of methylation at E158 (P = 0.0095);
MVP		0.74
MPC		0.38
ClinPred		0.064	T
GERP RS		3.0
Varity_R		0.13
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs1450025000; hg19: chrX-15536078; COSMIC: COSV105207250;