22-23181192-C-T

Position:

• chr22-23181192-C-T

Variant summary

Our verdict is Likely benign. Variant got -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

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 Likely_benign. Variant got -5 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCR	NM_004327.4	c.232C>T	p.Arg78Trp	missense_variant	1/23	ENST00000305877.13	NP_004318.3
BCR	NM_021574.3	c.232C>T	p.Arg78Trp	missense_variant	1/22		NP_067585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCR	ENST00000305877.13	c.232C>T	p.Arg78Trp	missense_variant	1/23	1	NM_004327.4	ENSP00000303507	P1
BCR	ENST00000359540.7	c.232C>T	p.Arg78Trp	missense_variant	1/22	1		ENSP00000352535
BCR	ENST00000479188.5	n.129+1360C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

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

Gnomad4 AFR exome AF: 0.0000407

Gnomad4 AMR exome AF: 0.0000929

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000834

Gnomad4 OTH exome AF: 0.0000441

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000637 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000124 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2022

The c.232C>T (p.R78W) alteration is located in exon 1 (coding exon 1) of the BCR gene. This alteration results from a C to T substitution at nucleotide position 232, causing the arginine (R) at amino acid position 78 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	0.60	N;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.99	D;D
Vest4		0.22
MutPred		0.62		Loss of disorder (P = 0.0206);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

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: rs761816882; hg19: chr22-23523379;