rs2227939

Positions:

• chr22-23289614-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004327.4(BCR):​c.2700T>C​(p.Asn900=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.29 in 1,612,806 control chromosomes in the GnomAD database, including 72,629 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 0.34 (10118 hom., cov: 34)
  • Exomes 𝑓: 0.28 (62511 hom.)
• Consequence: BCR NM_004327.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.579

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]

LOC107985554 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP7: Synonymous conserved (PhyloP=0.579 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCR	NM_004327.4	c.2700T>C	p.Asn900=	synonymous_variant	13/23	ENST00000305877.13	NP_004318.3
LOC107985554	XR_001755448.2	n.315+600A>G		intron_variant, non_coding_transcript_variant
BCR	NM_021574.3	c.2700T>C	p.Asn900=	synonymous_variant	13/22		NP_067585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCR	ENST00000305877.13	c.2700T>C	p.Asn900=	synonymous_variant	13/23	1	NM_004327.4	ENSP00000303507	P1
BCR	ENST00000359540.7	c.2700T>C	p.Asn900=	synonymous_variant	13/22	1		ENSP00000352535
BCR	ENST00000487968.5	n.1353T>C		non_coding_transcript_exon_variant	5/5	2
BCR	ENST00000419722.6			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52240 AN: 152022 Hom.: 10101 Cov.: 34

Gnomad AFR AF: 0.517

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.0605

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.189

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.344

GnomAD3 exomes AF: 0.286 AC: 71806 AN: 250794 Hom.: 11574 AF XY: 0.286 AC XY: 38820 AN XY: 135544

Gnomad AFR exome AF: 0.521

Gnomad AMR exome AF: 0.291

Gnomad ASJ exome AF: 0.378

Gnomad EAS exome AF: 0.0577

Gnomad SAS exome AF: 0.304

Gnomad FIN exome AF: 0.188

Gnomad NFE exome AF: 0.293

Gnomad OTH exome AF: 0.301

GnomAD4 exome AF: 0.284 AC: 415462 AN: 1460666 Hom.: 62511 Cov.: 34 AF XY: 0.286 AC XY: 207730 AN XY: 726666

Gnomad4 AFR exome AF: 0.538

Gnomad4 AMR exome AF: 0.303

Gnomad4 ASJ exome AF: 0.378

Gnomad4 EAS exome AF: 0.0610

Gnomad4 SAS exome AF: 0.306

Gnomad4 FIN exome AF: 0.196

Gnomad4 NFE exome AF: 0.283

Gnomad4 OTH exome AF: 0.297

GnomAD4 genome AF: 0.344 AC: 52304 AN: 152140 Hom.: 10118 Cov.: 34 AF XY: 0.336 AC XY: 24999 AN XY: 74396

Gnomad4 AFR AF: 0.517

Gnomad4 AMR AF: 0.326

Gnomad4 ASJ AF: 0.374

Gnomad4 EAS AF: 0.0604

Gnomad4 SAS AF: 0.286

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.291

Gnomad4 OTH AF: 0.341

Alfa AF: 0.321 Hom.: 5210

Bravo AF: 0.362

Asia WGS AF: 0.189 AC: 661 AN: 3478

EpiCase AF: 0.315

EpiControl AF: 0.318

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.8
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2227939; hg19: chr22-23631801; COSMIC: COSV59932322; COSMIC: COSV59932322;