Genetic Variant BCR:c.3013-6817C>T (chr22-23302607-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004327.4(BCR):c.3013-6817C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0989 in 152,362 control chromosomes in the GnomAD database, including 810 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.099 ( 810 hom., cov: 32)

Exomes 𝑓: 0.073 ( 0 hom. )

Consequence

BCR
NM_004327.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.06

Publications

6 publications found

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:

ENSG00000296232 (HGNC:):

ENSG00000296232 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCR	NM_004327.4 link	c.3013-6817C>T		intron_variant	Intron 16 of 22	ENST00000305877.13	NP_004318.3	P11274-1
BCR	NM_021574.3 link	c.2881-6817C>T		intron_variant	Intron 15 of 21		NP_067585.2	P11274-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCR	ENST00000305877.13 link	c.3013-6817C>T		intron_variant	Intron 16 of 22	1	NM_004327.4	ENSP00000303507.8		P11274-1

Frequencies

GnomAD3 genomes

AF:

0.0989

AC:

15039

AN:

152118

Hom.:

805

Cov.:

show subpopulations

Gnomad AFR

AF:

0.139

Gnomad AMI

AF:

0.145

Gnomad AMR

AF:

0.0803

Gnomad ASJ

AF:

0.0862

Gnomad EAS

AF:

0.0511

Gnomad SAS

AF:

0.0679

Gnomad FIN

AF:

0.0376

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.0942

Gnomad OTH

AF:

0.0956

GnomAD4 exome

AF:

0.0726

AC:

AN:

124

Hom.:

Cov.:

AF XY:

0.0745

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0612

AC:

AN:

Other (OTH)

AF:

0.0833

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0989

AC:

15055

AN:

152238

Hom.:

810

Cov.:

AF XY:

0.0950

AC XY:

7070

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.139

AC:

5757

AN:

41528

American (AMR)

AF:

0.0802

AC:

1227

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0862

AC:

299

AN:

3470

East Asian (EAS)

AF:

0.0514

AC:

266

AN:

5178

South Asian (SAS)

AF:

0.0671

AC:

324

AN:

4828

European-Finnish (FIN)

AF:

0.0376

AC:

399

AN:

10614

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0942

AC:

6407

AN:

67996

Other (OTH)

AF:

0.0960

AC:

203

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

709

1418

2128

2837

3546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

166

332

498

664

830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0954

Hom.:

2950

Bravo

AF:

0.106

Asia WGS

AF:

0.0770

AC:

267

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.14

(source)

DANN

Benign

0.69

PhyloP100

-4.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over