22-23181415-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004327.4(BCR):c.455C>T(p.Ala152Val) variant causes a missense change. The variant allele was found at a frequency of 0.0021 in 1,575,312 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts 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. A152T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0021 ( 15 hom. )

Consequence

BCR
NM_004327.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.47

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]

BCR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009052664).

BP6

Variant 22-23181415-C-T is Benign according to our data. Variant chr22-23181415-C-T is described in ClinVar as [Benign]. Clinvar id is 708500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 311 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCR	NM_004327.4 link	c.455C>T	p.Ala152Val	missense_variant	Exon 1 of 23	ENST00000305877.13	NP_004318.3	P11274-1
BCR	NM_021574.3 link	c.455C>T	p.Ala152Val	missense_variant	Exon 1 of 22		NP_067585.2	P11274-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BCR	ENST00000305877.13 link	c.455C>T	p.Ala152Val	missense_variant	Exon 1 of 23	1	NM_004327.4	ENSP00000303507.8	P11274-1
BCR	ENST00000359540.7 link	c.455C>T	p.Ala152Val	missense_variant	Exon 1 of 22	1		ENSP00000352535.3	P11274-2
BCR	ENST00000479188.5 link	n.129+1583C>T		intron_variant	Intron 1 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.00205

AC:

311

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0143

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00215

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00272

AC:

589

AN:

216466

Hom.:

AF XY:

0.00276

AC XY:

332

AN XY:

120122

show subpopulations

Gnomad AFR exome

AF:

0.000219

Gnomad AMR exome

AF:

0.0000332

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0150

Gnomad NFE exome

AF:

0.00303

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00211

AC:

3005

AN:

1423140

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

1483

AN XY:

703880

show subpopulations

Gnomad4 AFR exome

AF:

0.000217

Gnomad4 AMR exome

AF:

0.000123

Gnomad4 ASJ exome

AF:

0.0000412

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.0153

Gnomad4 NFE exome

AF:

0.00197

Gnomad4 OTH exome

AF:

0.00154

GnomAD4 genome

AF:

0.00204

AC:

311

AN:

152172

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

177

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0143

Gnomad4 NFE

AF:

0.00215

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00162

Hom.:

Bravo

AF:

0.000926

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000983

AC:

ExAC

AF:

0.00305

AC:

364

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BCR: BS1, BS2 -

Jul 23, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.0091

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

2.0

M;M

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.97

N;N

REVEL

Benign

0.15

Sift

Benign

0.072

T;T

Sift4G

Uncertain

0.0090

D;D

Polyphen

1.0

D;D

Vest4

0.60

MVP

0.56

MPC

0.73

ClinPred

0.043

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.16

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over