22-23181192-C-T

Variant names:

• chr22-23181192-C-T
• rs761816882
• NM_004327.4:c.232C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004327.4(BCR):​c.232C>T​(p.Arg78Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000716 in 1,173,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: BCR NM_004327.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.719
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.42306668).
• BS2: High AC in GnomAdExome4 at 84 AD gene.

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.232C>T	p.Arg78Trp	missense	Exon 1 of 23	NP_004318.3
	BCR	NM_021574.3		c.232C>T	p.Arg78Trp	missense	Exon 1 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.232C>T	p.Arg78Trp	missense	Exon 1 of 23	ENSP00000303507.8	P11274-1
	BCR	ENST00000359540.7	TSL:1	c.232C>T	p.Arg78Trp	missense	Exon 1 of 22	ENSP00000352535.3	P11274-2
	BCR	ENST00000928588.1		c.232C>T	p.Arg78Trp	missense	Exon 1 of 23	ENSP00000598647.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 1 AN: 83260 AF XY: 0.0000215

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000901

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000716 AC: 84 AN: 1173180 Hom.: 0 Cov.: 30 AF XY: 0.0000788 AC XY: 45 AN XY: 570792

African (AFR) AF: 0.0000407 AC: 1 AN: 24590

American (AMR) AF: 0.0000929 AC: 2 AN: 21518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18310

East Asian (EAS) AF: 0.00 AC: 0 AN: 25028

South Asian (SAS) AF: 0.00 AC: 0 AN: 46896

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4776

European-Non Finnish (NFE) AF: 0.0000834 AC: 79 AN: 947492

Other (OTH) AF: 0.0000441 AC: 2 AN: 45320

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000637 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000124 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.079
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.72
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.22
MutPred		0.62		Loss of disorder (P = 0.0206)
MVP		0.41
MPC		0.82
ClinPred		0.54	D
GERP RS		0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.083
gMVP		0.26
Mutation Taster		=79/21	polymorphism

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: rs761816882; hg19: chr22-23523379; COSMIC: COSV108114751; COSMIC: COSV108114751;