X-15516168-G-T

Variant names:

• chrX-15516168-G-T
• rs149800709
• NM_203281.3:c.382G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_203281.3(BMX):​c.382G>T​(p.Gly128Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,210,002 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G128G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: BMX NM_203281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.57
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203281.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMX	NM_203281.3	MANE Select	c.382G>T	p.Gly128Trp	missense	Exon 5 of 19	NP_975010.1	P51813
	BMX	NM_001721.7		c.382G>T	p.Gly128Trp	missense	Exon 5 of 19	NP_001712.1	P51813
	BMX	NM_001320866.2		c.382G>T	p.Gly128Trp	missense	Exon 5 of 19	NP_001307795.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMX	ENST00000348343.11	TSL:1 MANE Select	c.382G>T	p.Gly128Trp	missense	Exon 5 of 19	ENSP00000308774.6	P51813
	BMX	ENST00000342014.6	TSL:1	c.382G>T	p.Gly128Trp	missense	Exon 5 of 19	ENSP00000340082.6	P51813
	BMX	ENST00000357607.6	TSL:2	c.382G>T	p.Gly128Trp	missense	Exon 5 of 19	ENSP00000350224.2	P51813

Frequencies

GnomAD3 genomes AF: 0.00000887 AC: 1 AN: 112718 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1097284 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 1 AN XY: 362974

African (AFR) AF: 0.00 AC: 0 AN: 26355

American (AMR) AF: 0.00 AC: 0 AN: 35149

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19357

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 54078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4033

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841549

Other (OTH) AF: 0.00 AC: 0 AN: 46045

GnomAD4 genome AF: 0.00000887 AC: 1 AN: 112718 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34890

African (AFR) AF: 0.00 AC: 0 AN: 31041

American (AMR) AF: 0.00 AC: 0 AN: 10704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3572

South Asian (SAS) AF: 0.00 AC: 0 AN: 2751

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6251

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53301

Other (OTH) AF: 0.00 AC: 0 AN: 1522

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.88		Gain of ubiquitination at K129 (P = 0.0754)
MVP		0.99
MPC		1.2
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.81
gMVP		0.76
Mutation Taster		=89/11	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

Other links and lift over

dbSNP: rs149800709; hg19: chrX-15534291; COSMIC: COSV59592075;