X-15526092-A-T

Variant names:

• chrX-15526092-A-T
• rs1924710205
• NM_203281.3:c.881A>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_203281.3(BMX):​c.881A>T​(p.Tyr294Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000101 in 1,089,793 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 4 hem.)
• Consequence: BMX NM_203281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

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_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17385978).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMX	NM_203281.3	c.881A>T	p.Tyr294Phe	missense_variant	Exon 9 of 19	ENST00000348343.11	NP_975010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMX	ENST00000348343.11	c.881A>T	p.Tyr294Phe	missense_variant	Exon 9 of 19	1	NM_203281.3	ENSP00000308774.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000101 AC: 11 AN: 1089793 Hom.: 0 Cov.: 27 AF XY: 0.0000112 AC XY: 4 AN XY: 355585

African (AFR) AF: 0.00 AC: 0 AN: 26217

American (AMR) AF: 0.00 AC: 0 AN: 34938

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19276

East Asian (EAS) AF: 0.00 AC: 0 AN: 30094

South Asian (SAS) AF: 0.00 AC: 0 AN: 53163

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40443

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4107

European-Non Finnish (NFE) AF: 0.0000132 AC: 11 AN: 835748

Other (OTH) AF: 0.00 AC: 0 AN: 45807

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.881A>T (p.Y294F) alteration is located in exon 9 (coding exon 8) of the BMX gene. This alteration results from a A to T substitution at nucleotide position 881, causing the tyrosine (Y) at amino acid position 294 to be replaced by a phenylalanine (F). 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	0.095
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T;T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	.;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;N
PhyloP100		4.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.34	B;B;B
Vest4		0.32
MutPred		0.34		Loss of phosphorylation at Y294 (P = 0.0196);Loss of phosphorylation at Y294 (P = 0.0196);Loss of phosphorylation at Y294 (P = 0.0196);
MVP		0.67
MPC		0.35
ClinPred		0.40	T
GERP RS		5.5
Varity_R		0.26
gMVP		0.53
Mutation Taster		=78/22	polymorphism

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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Other links and lift over

dbSNP: rs1924710205; hg19: chrX-15544215;