chrX-15516168-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_203281.3(BMX):​c.382G>A​(p.Gly128Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000438 in 1,210,000 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G128W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000044 (0 hom. 16 hem.)
• Consequence: BMX NM_203281.3 missense
• Clinical Significance: Not reported in ClinVar
• 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_benign. The variant received -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• BS2: High Hemizygotes in GnomAdExome4 at 16 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMX	NM_203281.3	c.382G>A	p.Gly128Arg	missense_variant	Exon 5 of 19	ENST00000348343.11	NP_975010.1
BMX	NM_001721.7	c.382G>A	p.Gly128Arg	missense_variant	Exon 5 of 19		NP_001712.1
BMX	NM_001320866.2	c.382G>A	p.Gly128Arg	missense_variant	Exon 5 of 19		NP_001307795.1
BMX	XM_017029752.3	c.382G>A	p.Gly128Arg	missense_variant	Exon 5 of 16		XP_016885241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMX	ENST00000348343.11	c.382G>A	p.Gly128Arg	missense_variant	Exon 5 of 19	1	NM_203281.3	ENSP00000308774.6

Frequencies

GnomAD3 genomes AF: 0.0000444 AC: 5 AN: 112718 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000644

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: 0.0000563

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 183105 AF XY: 0.0000148

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000437 AC: 48 AN: 1097282 Hom.: 0 Cov.: 30 AF XY: 0.0000441 AC XY: 16 AN XY: 362974

African (AFR) AF: 0.0000379 AC: 1 AN: 26355

American (AMR) AF: 0.0000285 AC: 1 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: 0.0000547 AC: 46 AN: 841547

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

GnomAD4 genome AF: 0.0000444 AC: 5 AN: 112718 Hom.: 0 Cov.: 23 AF XY: 0.0000287 AC XY: 1 AN XY: 34890

African (AFR) AF: 0.0000644 AC: 2 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: 0.0000563 AC: 3 AN: 53301

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;D;D
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.93	.;.;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M;M;M
PhyloP100		6.6
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.2	D;D;D
REVEL	Pathogenic	0.87
Sift	Benign	0.037	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.84
MutPred		0.91		Gain of methylation at K129 (P = 0.0553);Gain of methylation at K129 (P = 0.0553);Gain of methylation at K129 (P = 0.0553);
MVP		0.99
MPC		1.2
ClinPred		0.86	D
GERP RS		5.4
Varity_R		0.70
gMVP		0.71
Mutation Taster		=95/5	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;