chrX-15509411-T-C

Variant names:

• chrX-15509411-T-C
• rs778275008
• NM_203281.3:c.221T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_203281.3(BMX):​c.221T>C​(p.Val74Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,089,554 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: BMX NM_203281.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09437841).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMX	NM_203281.3	c.221T>C	p.Val74Ala	missense_variant	Exon 3 of 19	ENST00000348343.11	NP_975010.1
BMX	NM_001721.7	c.221T>C	p.Val74Ala	missense_variant	Exon 3 of 19		NP_001712.1
BMX	NM_001320866.2	c.221T>C	p.Val74Ala	missense_variant	Exon 3 of 19		NP_001307795.1
BMX	XM_017029752.3	c.221T>C	p.Val74Ala	missense_variant	Exon 3 of 16		XP_016885241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMX	ENST00000348343.11	c.221T>C	p.Val74Ala	missense_variant	Exon 3 of 19	1	NM_203281.3	ENSP00000308774.6

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.00000562 AC: 1 AN: 177928 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000739

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1089554 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 355638

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26151

American (AMR) AF: 0.00 AC: 0 AN: 34782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19179

East Asian (EAS) AF: 0.00 AC: 0 AN: 30020

South Asian (SAS) AF: 0.00 AC: 0 AN: 53307

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4097

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 835957

Other (OTH) AF: 0.0000219 AC: 1 AN: 45741

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.221T>C (p.V74A) alteration is located in exon 3 (coding exon 2) of the BMX gene. This alteration results from a T to C substitution at nucleotide position 221, causing the valine (V) at amino acid position 74 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T;T;T
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.51	.;.;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.094	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	N;N;N
PhyloP100		1.1
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.36	N;N;N
REVEL	Benign	0.090
Sift	Benign	0.60	T;T;T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.14
MutPred		0.40		Gain of disorder (P = 0.0848);Gain of disorder (P = 0.0848);Gain of disorder (P = 0.0848);
MVP		0.64
MPC		0.41
ClinPred		0.037	T
GERP RS		4.4
Varity_R		0.069
gMVP		0.29
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: rs778275008; hg19: chrX-15527534;