rs180817

chr22-23315820-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004327.4(BCR):c.*298G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 478,156 control chromosomes in the GnomAD database, including 38,004 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 0.40 (12105 hom., cov: 31)
  • Exomes 𝑓: 0.39 (25899 hom.)
• Consequence: BCR NM_004327.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.904

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCR	NM_004327.4	c.*298G>A		3_prime_UTR_variant	23/23	ENST00000305877.13
BCR	NM_021574.3	c.*298G>A		3_prime_UTR_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCR	ENST00000305877.13	c.*298G>A		3_prime_UTR_variant	23/23	1	NM_004327.4	P1
BCR	ENST00000359540.7	c.*298G>A		3_prime_UTR_variant	22/22	1
BCR	ENST00000436990.2	n.1974G>A		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60178 AN: 151586 Hom.: 12092 Cov.: 31

Gnomad AFR AF: 0.412

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.594

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.378

GnomAD4 exome AF: 0.391 AC: 127607 AN: 326452 Hom.: 25899 Cov.: 0 AF XY: 0.388 AC XY: 66747 AN XY: 172242

Gnomad4 AFR exome AF: 0.415

Gnomad4 AMR exome AF: 0.385

Gnomad4 ASJ exome AF: 0.353

Gnomad4 EAS exome AF: 0.602

Gnomad4 SAS exome AF: 0.351

Gnomad4 FIN exome AF: 0.397

Gnomad4 NFE exome AF: 0.378

Gnomad4 OTH exome AF: 0.395

GnomAD4 genome AF: 0.397 AC: 60221 AN: 151704 Hom.: 12105 Cov.: 31 AF XY: 0.394 AC XY: 29248 AN XY: 74162

Gnomad4 AFR AF: 0.412

Gnomad4 AMR AF: 0.387

Gnomad4 ASJ AF: 0.366

Gnomad4 EAS AF: 0.594

Gnomad4 SAS AF: 0.378

Gnomad4 FIN AF: 0.382

Gnomad4 NFE AF: 0.381

Gnomad4 OTH AF: 0.383

Alfa AF: 0.393 Hom.: 1443

Bravo AF: 0.402

Asia WGS AF: 0.523 AC: 1818 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	14
Dann	Benign	0.74

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: rs180817; hg19: chr22-23658007; COSMIC: COSV59934993; COSMIC: COSV59934993;