X-15516168-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_203281.3(BMX):c.382G>T(p.Gly128Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,210,002 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 1 hem. )

Consequence

BMX
NM_203281.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.57

Publications

1 publications found

Variant links:

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]

BMX links:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMX	NM_203281.3 link	c.382G>T	p.Gly128Trp	missense_variant	Exon 5 of 19	ENST00000348343.11	NP_975010.1	P51813
BMX	NM_001721.7 link	c.382G>T	p.Gly128Trp	missense_variant	Exon 5 of 19		NP_001712.1	P51813
BMX	NM_001320866.2 link	c.382G>T	p.Gly128Trp	missense_variant	Exon 5 of 19		NP_001307795.1	P51813
BMX	XM_017029752.3 link	c.382G>T	p.Gly128Trp	missense_variant	Exon 5 of 16		XP_016885241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMX	ENST00000348343.11 link	c.382G>T	p.Gly128Trp	missense_variant	Exon 5 of 19	1	NM_203281.3	ENSP00000308774.6		P51813

Frequencies

GnomAD3 genomes

AF:

0.00000887

AC:

AN:

112718

Hom.:

Cov.:

show subpopulations

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000182

AC:

AN:

1097284

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362974

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26355

American (AMR)

AF:

0.00

AC:

AN:

35149

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19357

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

54078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4033

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841549

Other (OTH)

AF:

0.00

AC:

AN:

46045

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000887

AC:

AN:

112718

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34890

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31041

American (AMR)

AF:

0.00

AC:

AN:

10704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3572

South Asian (SAS)

AF:

0.00

AC:

AN:

2751

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6251

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53301

Other (OTH)

AF:

0.00

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.382G>T (p.G128W) alteration is located in exon 5 (coding exon 4) of the BMX gene. This alteration results from a G to T substitution at nucleotide position 382, causing the glycine (G) at amino acid position 128 to be replaced by a tryptophan (W). 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

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D;D

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.91

.;.;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M;M

PhyloP100

6.6

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-6.6

D;D;D

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.71

MutPred

0.88

Gain of ubiquitination at K129 (P = 0.0754);Gain of ubiquitination at K129 (P = 0.0754);Gain of ubiquitination at K129 (P = 0.0754);

MVP

0.99

MPC

1.2

ClinPred

1.0

GERP RS

5.4

Varity_R

0.81

gMVP

0.76

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

X-15516168-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over