22-23196511-T-C

Variant names:

• chr22-23196511-T-C
• rs5759636
• NM_004327.4:c.1279+14272T>C

Variant summary

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

The NM_004327.4(BCR):​c.1279+14272T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.859 in 152,180 control chromosomes in the GnomAD database, including 56,684 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 0.86 (56684 hom., cov: 31)
• Consequence: BCR NM_004327.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.134

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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCR	NM_004327.4	c.1279+14272T>C		intron_variant	Intron 1 of 22	ENST00000305877.13	NP_004318.3
BCR	NM_021574.3	c.1279+14272T>C		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.1279+14272T>C		intron_variant	Intron 1 of 22	1	NM_004327.4	ENSP00000303507.8
BCR	ENST00000359540.7	c.1279+14272T>C		intron_variant	Intron 1 of 21	1		ENSP00000352535.3
BCR	ENST00000479188.5	n.129+16679T>C		intron_variant	Intron 1 of 4	4

Frequencies

GnomAD3 genomes AF: 0.859 AC: 130645 AN: 152062 Hom.: 56623 Cov.: 31

Gnomad AFR AF: 0.965

Gnomad AMI AF: 0.863

Gnomad AMR AF: 0.855

Gnomad ASJ AF: 0.771

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.957

Gnomad FIN AF: 0.745

Gnomad MID AF: 0.847

Gnomad NFE AF: 0.801

Gnomad OTH AF: 0.842

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

GnomAD4 genome AF: 0.859 AC: 130763 AN: 152180 Hom.: 56684 Cov.: 31 AF XY: 0.861 AC XY: 64082 AN XY: 74394

Gnomad4 AFR AF: 0.965

Gnomad4 AMR AF: 0.855

Gnomad4 ASJ AF: 0.771

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.956

Gnomad4 FIN AF: 0.745

Gnomad4 NFE AF: 0.801

Gnomad4 OTH AF: 0.844

Alfa AF: 0.814 Hom.: 65393

Bravo AF: 0.868

Asia WGS AF: 0.979 AC: 3405 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.5
DANN	Benign	0.37

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: rs5759636; hg19: chr22-23538698;