Variant 22-23181457-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_004327.4(BCR):c.497G>A(p.Gly166Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,607,158 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 12 hom. )

Consequence

BCR
NM_004327.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.05

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005127102).

BP6

Variant 22-23181457-G-A is Benign according to our data. Variant chr22-23181457-G-A is described in ClinVar as [Benign]. Clinvar id is 720879.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 303 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCR	NM_004327.4 linkuse as main transcript	c.497G>A	p.Gly166Asp	missense_variant	1/23	ENST00000305877.13	NP_004318.3
BCR	NM_021574.3 linkuse as main transcript	c.497G>A	p.Gly166Asp	missense_variant	1/22		NP_067585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCR	ENST00000305877.13 linkuse as main transcript	c.497G>A	p.Gly166Asp	missense_variant	1/23	1	NM_004327.4	ENSP00000303507	P1	P11274-1
BCR	ENST00000359540.7 linkuse as main transcript	c.497G>A	p.Gly166Asp	missense_variant	1/22	1		ENSP00000352535		P11274-2
BCR	ENST00000479188.5 linkuse as main transcript	n.129+1625G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00199

AC:

303

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0109

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00245

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00308

AC:

742

AN:

241220

Hom.:

AF XY:

0.00298

AC XY:

394

AN XY:

132352

show subpopulations

Gnomad AFR exome

AF:

0.000532

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0126

Gnomad NFE exome

AF:

0.00408

Gnomad OTH exome

AF:

0.00419

GnomAD4 exome

AF:

0.00264

AC:

3846

AN:

1454844

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

1814

AN XY:

722766

show subpopulations

Gnomad4 AFR exome

AF:

0.000420

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0133

Gnomad4 NFE exome

AF:

0.00267

Gnomad4 OTH exome

AF:

0.00288

GnomAD4 genome

AF:

0.00199

AC:

303

AN:

152314

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0109

Gnomad4 NFE

AF:

0.00246

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00232

Hom.:

Bravo

AF:

0.00118

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00246

AC:

ExAC

AF:

0.00338

AC:

409

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.94

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.76

T;T

MetaRNN

Benign

0.0051

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.84

N;N

REVEL

Benign

0.030

Sift

Uncertain

0.0030

D;D

Sift4G

Benign

0.46

T;T

Polyphen

0.36

B;B

Vest4

0.13

MVP

0.41

MPC

0.52

ClinPred

0.030

GERP RS

-1.0

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.089

gMVP

0.24

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