22-23181165-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004327.4(BCR):ā€‹c.205A>Gā€‹(p.Ser69Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,416,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: š‘“ 0.0000067 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000024 ( 0 hom. )

Consequence

BCR
NM_004327.4 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.32
Variant links:
Genes affected
BCR (HGNC:1014): (BCR activator of RhoGEF and GTPase) A reciprocal translocation between chromosomes 22 and 9 produces the Philadelphia chromosome, which is often found in patients with chronic myelogenous leukemia. The chromosome 22 breakpoint for this translocation is located within the BCR gene. The translocation produces a fusion protein which is encoded by sequence from both BCR and ABL, the gene at the chromosome 9 breakpoint. Although the BCR-ABL fusion protein has been extensively studied, the function of the normal BCR gene product is not clear. The unregulated tyrosine kinase activity of BCR-ABL1 contributes to the immortality of leukaemic cells. The BCR protein has serine/threonine kinase activity and is a GTPase-activating protein for p21rac and other kinases. Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2020]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20866337).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BCRNM_004327.4 linkc.205A>G p.Ser69Gly missense_variant 1/23 ENST00000305877.13 NP_004318.3 P11274-1
BCRNM_021574.3 linkc.205A>G p.Ser69Gly missense_variant 1/22 NP_067585.2 P11274-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BCRENST00000305877.13 linkc.205A>G p.Ser69Gly missense_variant 1/231 NM_004327.4 ENSP00000303507.8 P11274-1
BCRENST00000359540.7 linkc.205A>G p.Ser69Gly missense_variant 1/221 ENSP00000352535.3 P11274-2
BCRENST00000479188.5 linkn.129+1333A>G intron_variant 4

Frequencies

GnomAD3 genomes
AF:
0.00000670
AC:
1
AN:
149268
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000149
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000833
AC:
1
AN:
120086
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
65240
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000206
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000237
AC:
3
AN:
1267100
Hom.:
0
Cov.:
30
AF XY:
0.00000481
AC XY:
3
AN XY:
623612
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000300
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000670
AC:
1
AN:
149268
Hom.:
0
Cov.:
32
AF XY:
0.0000137
AC XY:
1
AN XY:
72766
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000149
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000913
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 21, 2024The c.205A>G (p.S69G) alteration is located in exon 1 (coding exon 1) of the BCR gene. This alteration results from a A to G substitution at nucleotide position 205, causing the serine (S) at amino acid position 69 to be replaced by a glycine (G). 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
0.21
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
22
DANN
Uncertain
0.98
DEOGEN2
Benign
0.34
T;.
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.24
FATHMM_MKL
Benign
0.50
N
LIST_S2
Uncertain
0.88
D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.21
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.3
L;L
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.074
Sift
Benign
0.14
T;T
Sift4G
Benign
0.11
T;T
Polyphen
0.012
B;B
Vest4
0.43
MutPred
0.48
Loss of phosphorylation at S69 (P = 0.0132);Loss of phosphorylation at S69 (P = 0.0132);
MVP
0.47
MPC
0.62
ClinPred
0.26
T
GERP RS
3.8
Varity_R
0.089
gMVP
0.20

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs777423724; hg19: chr22-23523352; API