X-15522470-G-T

Variant names:

• chrX-15522470-G-T
• rs147917241
• NM_203281.3:c.635G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_203281.3(BMX):​c.635G>T​(p.Ser212Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,098,157 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign 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. S212R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000013 (0 hom. 7 hem.)
• Consequence: BMX NM_203281.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.758
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0867652).
• BS2: High Hemizygotes in GnomAdExome4 at 7 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.635G>T	p.Ser212Ile	missense	Exon 7 of 19	NP_975010.1	P51813
	BMX	NM_001721.7		c.635G>T	p.Ser212Ile	missense	Exon 7 of 19	NP_001712.1	P51813
	BMX	NM_001320866.2		c.635G>T	p.Ser212Ile	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.635G>T	p.Ser212Ile	missense	Exon 7 of 19	ENSP00000308774.6	P51813
	BMX	ENST00000342014.6	TSL:1	c.635G>T	p.Ser212Ile	missense	Exon 7 of 19	ENSP00000340082.6	P51813
	BMX	ENST00000357607.6	TSL:2	c.635G>T	p.Ser212Ile	missense	Exon 7 of 19	ENSP00000350224.2	P51813

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000127 AC: 14 AN: 1098157 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 7 AN XY: 363547

African (AFR) AF: 0.00 AC: 0 AN: 26396

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30202

South Asian (SAS) AF: 0.00 AC: 0 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000166 AC: 14 AN: 842079

Other (OTH) AF: 0.00 AC: 0 AN: 46089

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.94
DANN	Benign	0.33
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.76
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.21
Sift	Benign	0.24	T
Sift4G	Benign	0.19	T
Polyphen		0.68	P
Vest4		0.072
MutPred		0.31		Loss of phosphorylation at S212 (P = 0.0147)
MVP		0.56
MPC		0.40
ClinPred		0.23	T
GERP RS		-0.47
Varity_R		0.11
gMVP		0.17
Mutation Taster		=99/1	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: rs147917241; hg19: chrX-15540593;