rs527236143

Variant names:

• chr22-23290381-T-A
• rs527236143
• NM_004327.4:c.2750T>A

Your query was ambiguous. Multiple possible variants found:

• chr22-23290381-T-A
• chr22-23290381-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004327.4(BCR):​c.2750T>A​(p.Val917Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BCR NM_004327.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.77
• Publications: 1 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]

ENSG00000296232 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004327.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCR	NM_004327.4	MANE Select	c.2750T>A	p.Val917Asp	missense	Exon 14 of 23	NP_004318.3
	BCR	NM_021574.3		c.2750T>A	p.Val917Asp	missense	Exon 14 of 22	NP_067585.2	P11274-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCR	ENST00000305877.13	TSL:1 MANE Select	c.2750T>A	p.Val917Asp	missense	Exon 14 of 23	ENSP00000303507.8	P11274-1
	BCR	ENST00000359540.7	TSL:1	c.2750T>A	p.Val917Asp	missense	Exon 14 of 22	ENSP00000352535.3	P11274-2
	BCR	ENST00000928588.1		c.2771T>A	p.Val924Asp	missense	Exon 14 of 23	ENSP00000598647.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Chronic myelogenous leukemia, BCR-ABL1 positive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.79		Loss of sheet (P = 0.0181)
MVP		0.97
MPC		1.5
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.95
gMVP		0.95
Mutation Taster		=18/82	disease causing

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: rs527236143; hg19: chr22-23632568;