X-15522476-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 14/19 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, single submitter B:1
• Conservation: PhyloP100: 0.756

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

Verdict is Benign. Variant got -14 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 id is 728813.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome 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 gnomad4_exome. There are 893 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMX	NM_203281.3	c.641C>T	p.Ala214Val	missense_variant	7/19	ENST00000348343.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMX	ENST00000348343.11	c.641C>T	p.Ala214Val	missense_variant	7/19	1	NM_203281.3	P1

Frequencies

GnomAD3 genomes AF: 0.000958 AC: 108 AN: 112762 Hom.: 2 Cov.: 23 AF XY: 0.00135 AC XY: 47 AN XY: 34912

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

GnomAD3 exomes AF: 0.00259 AC: 475 AN: 183137 Hom.: 3 AF XY: 0.00396 AC XY: 268 AN XY: 67727

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 SAS exome AF: 0.0212

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

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.000227

Gnomad4 ASJ exome AF: 0.000103

Gnomad4 EAS exome AF: 0.000132

Gnomad4 SAS exome AF: 0.0222

Gnomad4 FIN exome AF: 0.000271

Gnomad4 NFE exome AF: 0.000365

Gnomad4 OTH exome AF: 0.00189

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

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00112

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000280

Gnomad4 SAS AF: 0.0181

Gnomad4 FIN AF: 0.000481

Gnomad4 NFE AF: 0.000525

Gnomad4 OTH AF: 0.00259

Alfa AF: 0.000660 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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 19, 2017

- -

Computational scores

Source: dbNSFP v4.3

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;T;T
FATHMM_MKL	Benign	0.25	N
MetaRNN	Benign	0.0054	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.97	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.96	D;D;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

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

Publications

LitVar

Other links and lift over

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