X-15522476-C-T

Variant names:

• chrX-15522476-C-T
• rs139052738
• NM_203281.3:c.641C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_203281.3(BMX):​c.641C>T​(p.Ala214Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,210,948 control chromosomes in the GnomAD database, including 17 homozygotes. There are 940 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A214T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00095 (2 hom., 47 hem., cov: 23)
  • Exomes 𝑓: 0.0015 (15 hom. 893 hem.)
• Consequence: BMX NM_203281.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.756
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005443424).
• BP6: Variant X-15522476-C-T is Benign according to our data. Variant chrX-15522476-C-T is described in ClinVar as Benign. ClinVar VariationId is 728813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00153 (1681/1098132) while in subpopulation SAS AF = 0.0222 (1202/54147). AF 95% confidence interval is 0.0212. There are 15 homozygotes in GnomAdExome4. There are 893 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.641C>T	p.Ala214Val	missense	Exon 7 of 19	NP_975010.1	P51813
	BMX	NM_001721.7		c.641C>T	p.Ala214Val	missense	Exon 7 of 19	NP_001712.1	P51813
	BMX	NM_001320866.2		c.641C>T	p.Ala214Val	missense	Exon 7 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.641C>T	p.Ala214Val	missense	Exon 7 of 19	ENSP00000308774.6	P51813
	BMX	ENST00000342014.6	TSL:1	c.641C>T	p.Ala214Val	missense	Exon 7 of 19	ENSP00000340082.6	P51813
	BMX	ENST00000357607.6	TSL:2	c.641C>T	p.Ala214Val	missense	Exon 7 of 19	ENSP00000350224.2	P51813

Frequencies

GnomAD3 genomes AF: 0.000958 AC: 108 AN: 112762 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.0181

Gnomad FIN AF: 0.000481

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.000525

Gnomad OTH AF: 0.00262

GnomAD2 exomes AF: 0.00259 AC: 475 AN: 183137 AF XY: 0.00396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad FIN exome AF: 0.000312

Gnomad NFE exome AF: 0.000612

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00153 AC: 1681 AN: 1098132 Hom.: 15 Cov.: 32 AF XY: 0.00246 AC XY: 893 AN XY: 363524

African (AFR) AF: 0.0000758 AC: 2 AN: 26397

American (AMR) AF: 0.000227 AC: 8 AN: 35186

Ashkenazi Jewish (ASJ) AF: 0.000103 AC: 2 AN: 19383

East Asian (EAS) AF: 0.000132 AC: 4 AN: 30202

South Asian (SAS) AF: 0.0222 AC: 1202 AN: 54147

European-Finnish (FIN) AF: 0.000271 AC: 11 AN: 40531

Middle Eastern (MID) AF: 0.0140 AC: 58 AN: 4135

European-Non Finnish (NFE) AF: 0.000365 AC: 307 AN: 842058

Other (OTH) AF: 0.00189 AC: 87 AN: 46093

GnomAD4 genome AF: 0.000948 AC: 107 AN: 112816 Hom.: 2 Cov.: 23 AF XY: 0.00134 AC XY: 47 AN XY: 34976

African (AFR) AF: 0.000193 AC: 6 AN: 31092

American (AMR) AF: 0.00112 AC: 12 AN: 10688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.000280 AC: 1 AN: 3574

South Asian (SAS) AF: 0.0181 AC: 50 AN: 2756

European-Finnish (FIN) AF: 0.000481 AC: 3 AN: 6242

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 217

European-Non Finnish (NFE) AF: 0.000525 AC: 28 AN: 53360

Other (OTH) AF: 0.00259 AC: 4 AN: 1545

Alfa AF: 0.000613 Hom.: 31

Bravo AF: 0.000627

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.00310 AC: 376

EpiCase AF: 0.00104

EpiControl AF: 0.00154

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.2
DANN	Benign	0.87
DEOGEN2	Benign	0.38	T
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.76
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.16
Sift	Benign	0.14	T
Sift4G	Benign	0.24	T
Polyphen		0.96	D
Vest4		0.052
MVP		0.66
MPC		0.34
ClinPred		0.014	T
GERP RS		0.23
Varity_R		0.089
gMVP		0.46
Mutation Taster		=100/0	polymorphism (auto)

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: rs139052738; hg19: chrX-15540599; COSMIC: COSV105909525; COSMIC: COSV105909525;