X-15534212-T-G

Variant names:

• chrX-15534212-T-G
• rs1601651847
• NM_203281.3:c.1020T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_203281.3(BMX):​c.1020T>G​(p.Asn340Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000962 in 1,039,742 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N340N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.6e-7 (0 hom. 0 hem.)
• Consequence: BMX NM_203281.3 missense, splice_region
• Scores: Splicing: ADA: 0.002324
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.678
• Publications: 0 publications found

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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1680485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMX	NM_203281.3	c.1020T>G	p.Asn340Lys	missense_variant, splice_region_variant	Exon 12 of 19	ENST00000348343.11	NP_975010.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMX	ENST00000348343.11	c.1020T>G	p.Asn340Lys	missense_variant, splice_region_variant	Exon 12 of 19	1	NM_203281.3	ENSP00000308774.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.62e-7 AC: 1 AN: 1039742 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 327352

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000424 AC: 1 AN: 23577

American (AMR) AF: 0.00 AC: 0 AN: 27843

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17845

East Asian (EAS) AF: 0.00 AC: 0 AN: 27815

South Asian (SAS) AF: 0.00 AC: 0 AN: 45715

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3898

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 809905

Other (OTH) AF: 0.00 AC: 0 AN: 43620

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000509 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	16
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.49	T;T;T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.55	.;.;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.42	N;N;N
PhyloP100		0.68
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.14
Sift	Benign	0.074	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.12
MutPred		0.51		Gain of methylation at N340 (P = 8e-04);Gain of methylation at N340 (P = 8e-04);Gain of methylation at N340 (P = 8e-04);
MVP		0.78
MPC		0.39
ClinPred		0.24	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.44
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0023
dbscSNV1_RF	Benign	0.12
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

Other links and lift over

dbSNP: rs1601651847; hg19: chrX-15552335;