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GeneBe

22-23181460-A-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004327.4(BCR):c.500A>C(p.Gln167Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000311 in 1,607,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

BCR
NM_004327.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.047361195).
BS2
High AC in GnomAd at 30 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BCRNM_004327.4 linkuse as main transcriptc.500A>C p.Gln167Pro missense_variant 1/23 ENST00000305877.13
BCRNM_021574.3 linkuse as main transcriptc.500A>C p.Gln167Pro missense_variant 1/22

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BCRENST00000305877.13 linkuse as main transcriptc.500A>C p.Gln167Pro missense_variant 1/231 NM_004327.4 P1P11274-1
BCRENST00000359540.7 linkuse as main transcriptc.500A>C p.Gln167Pro missense_variant 1/221 P11274-2
BCRENST00000479188.5 linkuse as main transcriptn.129+1628A>C intron_variant, non_coding_transcript_variant 4

Frequencies

GnomAD3 genomes
AF:
0.000197
AC:
30
AN:
152162
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00157
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:
0.00
Gnomad OTH
AF:
0.00239
GnomAD3 exomes
AF:
0.0000165
AC:
4
AN:
241738
Hom.:
0
AF XY:
0.0000226
AC XY:
3
AN XY:
132632
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:
0.0000660
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000335
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1455240
Hom.:
0
Cov.:
33
AF XY:
0.0000152
AC XY:
11
AN XY:
722964
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000180
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000233
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.000197
AC:
30
AN:
152280
Hom.:
0
Cov.:
33
AF XY:
0.000242
AC XY:
18
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00157
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00236
Bravo
AF:
0.000321
ExAC
AF:
0.0000165
AC:
2

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 GeneticsFeb 05, 2024The c.500A>C (p.Q167P) alteration is located in exon 1 (coding exon 1) of the BCR gene. This alteration results from a A to C substitution at nucleotide position 500, causing the glutamine (Q) at amino acid position 167 to be replaced by a proline (P). 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
0.066
BayesDel_addAF
Benign
-0.36
T
BayesDel_noAF
Benign
-0.58
Cadd
Benign
16
Dann
Benign
0.58
DEOGEN2
Benign
0.28
T;.
Eigen
Benign
-0.97
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.69
D
LIST_S2
Benign
0.65
T;T
M_CAP
Benign
0.0078
T
MetaRNN
Benign
0.047
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.69
N;N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.060
Sift
Benign
0.16
T;T
Sift4G
Benign
0.10
T;T
Polyphen
0.0
B;B
Vest4
0.17
MutPred
0.28
Gain of catalytic residue at Q167 (P = 0.0198);Gain of catalytic residue at Q167 (P = 0.0198);
MVP
0.33
MPC
0.47
ClinPred
0.020
T
GERP RS
-3.5
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.8
Varity_R
0.12
gMVP
0.27

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: rs553473471; hg19: chr22-23523647; API