X-15542204-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_203281.3(BMX):c.1611+6C>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,205,167 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 78 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., 13 hem., cov: 23)
  • Exomes 𝑓: 0.00019 (0 hom. 65 hem.)
• Consequence: BMX NM_203281.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.002029
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.458

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant X-15542204-C-A is Benign according to our data. Variant chrX-15542204-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2660055.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMX	NM_203281.3	c.1611+6C>A		splice_donor_region_variant, intron_variant		ENST00000348343.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMX	ENST00000348343.11	c.1611+6C>A		splice_donor_region_variant, intron_variant		1	NM_203281.3	P1

Frequencies

GnomAD3 genomes AF: 0.000403 AC: 45 AN: 111730 Hom.: 0 Cov.: 23 AF XY: 0.000442 AC XY: 15 AN XY: 33906

Gnomad AFR AF: 0.000879

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000667

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000169

Gnomad OTH AF: 0.000666

GnomAD3 exomes AF: 0.000264 AC: 48 AN: 181742 Hom.: 0 AF XY: 0.000240 AC XY: 16 AN XY: 66756

Gnomad AFR exome AF: 0.000765

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000198

Gnomad OTH exome AF: 0.000893

GnomAD4 exome AF: 0.000193 AC: 211 AN: 1093385 Hom.: 0 Cov.: 29 AF XY: 0.000181 AC XY: 65 AN XY: 359121

Gnomad4 AFR exome AF: 0.000533

Gnomad4 AMR exome AF: 0.000256

Gnomad4 ASJ exome AF: 0.000725

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000171

Gnomad4 OTH exome AF: 0.000436

GnomAD4 genome AF: 0.000394 AC: 44 AN: 111782 Hom.: 0 Cov.: 23 AF XY: 0.000383 AC XY: 13 AN XY: 33968

Gnomad4 AFR AF: 0.000845

Gnomad4 AMR AF: 0.000666

Gnomad4 ASJ AF: 0.000377

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000169

Gnomad4 OTH AF: 0.000658

Alfa AF: 0.000478 Hom.: 2

Bravo AF: 0.000638

EpiCase AF: 0.000109

EpiControl AF: 0.000357

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

BMX: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	14
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0020
dbscSNV1_RF	Benign	0.070
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

Other links and lift over

dbSNP: rs370079442; hg19: chrX-15560327;