22-23181355-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004327.4(BCR):c.395G>C(p.Arg132Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,505,872 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R132L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: BCR NM_004327.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.71

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020543933).
• BP6: Variant 22-23181355-G-C is Benign according to our data. Variant chr22-23181355-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 725929.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 110 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCR	NM_004327.4	c.395G>C	p.Arg132Pro	missense_variant	1/23	ENST00000305877.13
BCR	NM_021574.3	c.395G>C	p.Arg132Pro	missense_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCR	ENST00000305877.13	c.395G>C	p.Arg132Pro	missense_variant	1/23	1	NM_004327.4	P1
BCR	ENST00000359540.7	c.395G>C	p.Arg132Pro	missense_variant	1/22	1
BCR	ENST00000479188.5	n.129+1523G>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.000725 AC: 110 AN: 151762 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

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: 0.000191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000751 AC: 102 AN: 135790 Hom.: 1 AF XY: 0.000725 AC XY: 55 AN XY: 75826

Gnomad AFR exome AF: 0.000223

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: 0.00149

Gnomad OTH exome AF: 0.000915

GnomAD4 exome AF: 0.00118 AC: 1600 AN: 1353998 Hom.: 2 Cov.: 31 AF XY: 0.00112 AC XY: 743 AN XY: 665766

Gnomad4 AFR exome AF: 0.000137

Gnomad4 AMR exome AF: 0.0000341

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000280

Gnomad4 FIN exome AF: 0.000101

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.000915

GnomAD4 genome AF: 0.000724 AC: 110 AN: 151874 Hom.: 0 Cov.: 32 AF XY: 0.000579 AC XY: 43 AN XY: 74256

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000191

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.000695

ExAC AF: 0.000685 AC: 75

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Apr 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.021	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.17
Sift	Benign	0.14	T;T
Sift4G	Benign	0.068	T;T
Polyphen		0.0010	B;B
Vest4		0.28
MVP		0.65
MPC		0.55
ClinPred		0.020	T
GERP RS		3.3
Varity_R		0.11
gMVP		0.30

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

Other links and lift over

dbSNP: rs200084105; hg19: chr22-23523542; COSMIC: COSV59935016; COSMIC: COSV59935016;