22-23226671-A-G

Variant names:

• chr22-23226671-A-G
• rs762601
• NM_004327.4:c.1280-27128A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004327.4(BCR):​c.1280-27128A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.595 in 152,068 control chromosomes in the GnomAD database, including 27,718 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 0.59 (27718 hom., cov: 33)
• Consequence: BCR NM_004327.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.27
• Publications: 9 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCR	NM_004327.4	c.1280-27128A>G		intron_variant	Intron 1 of 22	ENST00000305877.13	NP_004318.3
BCR	NM_021574.3	c.1280-27128A>G		intron_variant	Intron 1 of 21		NP_067585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCR	ENST00000305877.13	c.1280-27128A>G		intron_variant	Intron 1 of 22	1	NM_004327.4	ENSP00000303507.8

Frequencies

GnomAD3 genomes AF: 0.595 AC: 90362 AN: 151950 Hom.: 27670 Cov.: 33

Gnomad AFR AF: 0.743

Gnomad AMI AF: 0.621

Gnomad AMR AF: 0.576

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.602

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.528

Gnomad OTH AF: 0.580

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

GnomAD4 genome AF: 0.595 AC: 90465 AN: 152068 Hom.: 27718 Cov.: 33 AF XY: 0.591 AC XY: 43925 AN XY: 74336

African (AFR) AF: 0.744 AC: 30818 AN: 41448

American (AMR) AF: 0.576 AC: 8802 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1698 AN: 3470

East Asian (EAS) AF: 0.712 AC: 3690 AN: 5180

South Asian (SAS) AF: 0.601 AC: 2900 AN: 4826

European-Finnish (FIN) AF: 0.444 AC: 4691 AN: 10560

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.528 AC: 35920 AN: 67976

Other (OTH) AF: 0.584 AC: 1234 AN: 2114

Alfa AF: 0.552 Hom.: 100343

Bravo AF: 0.612

Asia WGS AF: 0.679 AC: 2362 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.20
DANN	Benign	0.44
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs762601; hg19: chr22-23568858;