X-15522476-C-T

Position:

chrX-15522476-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000348343.11(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. 14/19 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
ENST00000348343.11 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.756

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. gnomad4_exome 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 gnomad4_exome. There are 893 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMX	NM_203281.3 linkuse as main transcript	c.641C>T	p.Ala214Val	missense_variant	7/19	ENST00000348343.11	NP_975010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMX	ENST00000348343.11 linkuse as main transcript	c.641C>T	p.Ala214Val	missense_variant	7/19	1	NM_203281.3	ENSP00000308774	P1

Frequencies

GnomAD3 genomes

AF:

0.000958

AC:

108

AN:

112762

Hom.:

Cov.:

AF XY:

0.00135

AC XY:

AN XY:

34912

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

GnomAD3 exomes

AF:

0.00259

AC:

475

AN:

183137

Hom.:

AF XY:

0.00396

AC XY:

268

AN XY:

67727

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 SAS exome

AF:

0.0212

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

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.000103

Gnomad4 EAS exome

AF:

0.000132

Gnomad4 SAS exome

AF:

0.0222

Gnomad4 FIN exome

AF:

0.000271

Gnomad4 NFE exome

AF:

0.000365

Gnomad4 OTH exome

AF:

0.00189

GnomAD4 genome

AF:

0.000948

AC:

107

AN:

112816

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

AN XY:

34976

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00112

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000280

Gnomad4 SAS

AF:

0.0181

Gnomad4 FIN

AF:

0.000481

Gnomad4 NFE

AF:

0.000525

Gnomad4 OTH

AF:

0.00259

Alfa

AF:

0.000660

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2017	- -

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

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

MutationTaster

Benign

1.0

N;N;N

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over