rs16997078

Positions:

• chrX-15546689-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_203281.3(BMX):​c.1677-114A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0251 in 544,673 control chromosomes in the GnomAD database, including 905 homozygotes. There are 3,997 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.068 (608 hom., 2121 hem., cov: 23)
  • Exomes 𝑓: 0.014 (297 hom. 1876 hem.)
• Consequence: BMX NM_203281.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0180

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMX	NM_203281.3	c.1677-114A>G		intron_variant		ENST00000348343.11	NP_975010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMX	ENST00000348343.11	c.1677-114A>G		intron_variant		1	NM_203281.3	ENSP00000308774	P1

Frequencies

GnomAD3 genomes AF: 0.0675 AC: 7539 AN: 111734 Hom.: 609 Cov.: 23 AF XY: 0.0621 AC XY: 2107 AN XY: 33918

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0315

Gnomad SAS AF: 0.0620

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.0252

Gnomad NFE AF: 0.000751

Gnomad OTH AF: 0.0579

GnomAD4 exome AF: 0.0142 AC: 6130 AN: 432882 Hom.: 297 AF XY: 0.0154 AC XY: 1876 AN XY: 121746

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.0158

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0369

Gnomad4 SAS exome AF: 0.0565

Gnomad4 FIN exome AF: 0.000289

Gnomad4 NFE exome AF: 0.000739

Gnomad4 OTH exome AF: 0.0256

GnomAD4 genome AF: 0.0676 AC: 7552 AN: 111791 Hom.: 608 Cov.: 23 AF XY: 0.0624 AC XY: 2121 AN XY: 33983

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.0264

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0313

Gnomad4 SAS AF: 0.0629

Gnomad4 FIN AF: 0.000164

Gnomad4 NFE AF: 0.000751

Gnomad4 OTH AF: 0.0572

Alfa AF: 0.0514 Hom.: 191

Bravo AF: 0.0763

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.4
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs16997078; hg19: chrX-15564812;