rs5751614

Positions:

• chr22-23250864-G-A
• chr22-23250864-G-C

Variant summary

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

The NM_004327.4(BCR):​c.1280-2935G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 152,008 control chromosomes in the GnomAD database, including 22,482 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 0.54 (22482 hom., cov: 32)
• Consequence: BCR NM_004327.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.910

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=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCR	NM_004327.4	c.1280-2935G>A		intron_variant		ENST00000305877.13
BCR	NM_021574.3	c.1280-2935G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCR	ENST00000305877.13	c.1280-2935G>A		intron_variant		1	NM_004327.4	P1

Frequencies

GnomAD3 genomes AF: 0.536 AC: 81354 AN: 151890 Hom.: 22439 Cov.: 32

Gnomad AFR AF: 0.675

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.503

Gnomad EAS AF: 0.571

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.529

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.536 AC: 81456 AN: 152008 Hom.: 22482 Cov.: 32 AF XY: 0.531 AC XY: 39464 AN XY: 74310

Gnomad4 AFR AF: 0.675

Gnomad4 AMR AF: 0.501

Gnomad4 ASJ AF: 0.503

Gnomad4 EAS AF: 0.571

Gnomad4 SAS AF: 0.561

Gnomad4 FIN AF: 0.409

Gnomad4 NFE AF: 0.475

Gnomad4 OTH AF: 0.534

Alfa AF: 0.493 Hom.: 42008

Bravo AF: 0.549

Asia WGS AF: 0.615 AC: 2139 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.60
DANN	Benign	0.62

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: rs5751614; hg19: chr22-23593051;