NM_203281.3:c.1711G>A

Variant names:

• chrX-15546837-G-A
• rs144206884
• NM_203281.3:c.1711G>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.1711G>A​(p.Gly571Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000191 in 1,097,013 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000019 (0 hom. 10 hem.)
• Consequence: BMX NM_203281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.15
• Publications: 2 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, 0.916
• BS2: High Hemizygotes in GnomAdExome4 at 10 gene

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.1711G>A	p.Gly571Arg	missense	Exon 17 of 19	NP_975010.1	P51813
	BMX	NM_001721.7		c.1711G>A	p.Gly571Arg	missense	Exon 17 of 19	NP_001712.1	P51813
	BMX	NM_001320866.2		c.1708G>A	p.Gly570Arg	missense	Exon 17 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.1711G>A	p.Gly571Arg	missense	Exon 17 of 19	ENSP00000308774.6	P51813
	BMX	ENST00000342014.6	TSL:1	c.1711G>A	p.Gly571Arg	missense	Exon 17 of 19	ENSP00000340082.6	P51813
	BMX	ENST00000357607.6	TSL:2	c.1711G>A	p.Gly571Arg	missense	Exon 17 of 19	ENSP00000350224.2	P51813

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000110 AC: 2 AN: 181854 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

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: 0.0000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000191 AC: 21 AN: 1097013 Hom.: 0 Cov.: 29 AF XY: 0.0000276 AC XY: 10 AN XY: 362529

African (AFR) AF: 0.0000759 AC: 2 AN: 26357

American (AMR) AF: 0.00 AC: 0 AN: 35123

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19363

East Asian (EAS) AF: 0.00 AC: 0 AN: 30141

South Asian (SAS) AF: 0.00 AC: 0 AN: 54038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40499

Middle Eastern (MID) AF: 0.000727 AC: 3 AN: 4126

European-Non Finnish (NFE) AF: 0.0000190 AC: 16 AN: 841314

Other (OTH) AF: 0.00 AC: 0 AN: 46052

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

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	0.96
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.89		Gain of methylation at G571 (P = 0.0314)
MVP		0.99
MPC		1.2
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.91
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.33		Position offset: -34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144206884; hg19: chrX-15564960; COSMIC: COSV59594281;