X-15522476-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_203281.3(BMX):c.641C>T(p.Ala214Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,210,948 control chromosomes in the GnomAD database, including 17 homozygotes. There are 940 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A214T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00095 ( 2 hom., 47 hem., cov: 23)

Exomes 𝑓: 0.0015 ( 15 hom. 893 hem. )

Consequence

BMX
NM_203281.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.756

Publications

0 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005443424).

BP6

Variant X-15522476-C-T is Benign according to our data. Variant chrX-15522476-C-T is described in ClinVar as [Benign]. Clinvar id is 728813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00153 (1681/1098132) while in subpopulation SAS AF = 0.0222 (1202/54147). AF 95% confidence interval is 0.0212. There are 15 homozygotes in GnomAdExome4. There are 893 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMX	NM_203281.3 link	c.641C>T	p.Ala214Val	missense_variant	Exon 7 of 19	ENST00000348343.11	NP_975010.1	P51813

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMX	ENST00000348343.11 link	c.641C>T	p.Ala214Val	missense_variant	Exon 7 of 19	1	NM_203281.3	ENSP00000308774.6		P51813

Frequencies

GnomAD3 genomes

AF:

0.000958

AC:

108

AN:

112762

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00112

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.0181

Gnomad FIN

AF:

0.000481

Gnomad MID

AF:

0.0168

Gnomad NFE

AF:

0.000525

Gnomad OTH

AF:

0.00262

GnomAD2 exomes

AF:

0.00259

AC:

475

AN:

183137

AF XY:

0.00396

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000256

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad FIN exome

AF:

0.000312

Gnomad NFE exome

AF:

0.000612

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00153

AC:

1681

AN:

1098132

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

893

AN XY:

363524

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26397

American (AMR)

AF:

0.000227

AC:

AN:

35186

Ashkenazi Jewish (ASJ)

AF:

0.000103

AC:

AN:

19383

East Asian (EAS)

AF:

0.000132

AC:

AN:

30202

South Asian (SAS)

AF:

0.0222

AC:

1202

AN:

54147

European-Finnish (FIN)

AF:

0.000271

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.0140

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.000365

AC:

307

AN:

842058

Other (OTH)

AF:

0.00189

AC:

AN:

46093

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000948

AC:

107

AN:

112816

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

AN XY:

34976

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

31092

American (AMR)

AF:

0.00112

AC:

AN:

10688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.000280

AC:

AN:

3574

South Asian (SAS)

AF:

0.0181

AC:

AN:

2756

European-Finnish (FIN)

AF:

0.000481

AC:

AN:

6242

Middle Eastern (MID)

AF:

0.0138

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.000525

AC:

AN:

53360

Other (OTH)

AF:

0.00259

AC:

AN:

1545

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000613

Hom.:

Bravo

AF:

0.000627

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000892

AC:

ExAC

AF:

0.00310

AC:

376

EpiCase

AF:

0.00104

EpiControl

AF:

0.00154

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 19, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

4.2

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.38

T;T;T

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.61

.;.;T

MetaRNN

Benign

0.0054

T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.34

N;N;N

PhyloP100

0.76

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.97

N;N;N

REVEL

Benign

0.16

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.96

D;D;D

Vest4

0.052

MVP

0.66

MPC

0.34

ClinPred

0.014

GERP RS

0.23

Varity_R

0.089

gMVP

0.46

Mutation Taster

=100/0

polymorphism (auto)

(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

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X-15522476-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over