chr22-23181415-C-T

Position:

• chr22-23181415-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004327.4(BCR):​c.455C>T​(p.Ala152Val) variant causes a missense change. The variant allele was found at a frequency of 0.0021 in 1,575,312 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (15 hom.)
• Consequence: BCR NM_004327.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.47

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]

BCR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009052664).
• BP6: Variant 22-23181415-C-T is Benign according to our data. Variant chr22-23181415-C-T is described in ClinVar as [Benign]. Clinvar id is 708500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 311 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCR	NM_004327.4	c.455C>T	p.Ala152Val	missense_variant	1/23	ENST00000305877.13	NP_004318.3
BCR	NM_021574.3	c.455C>T	p.Ala152Val	missense_variant	1/22		NP_067585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCR	ENST00000305877.13	c.455C>T	p.Ala152Val	missense_variant	1/23	1	NM_004327.4	ENSP00000303507.8
BCR	ENST00000359540.7	c.455C>T	p.Ala152Val	missense_variant	1/22	1		ENSP00000352535.3
BCR	ENST00000479188.5	n.129+1583C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 311 AN: 152056 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0143

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00272 AC: 589 AN: 216466 Hom.: 5 AF XY: 0.00276 AC XY: 332 AN XY: 120122

Gnomad AFR exome AF: 0.000219

Gnomad AMR exome AF: 0.0000332

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.00303

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00211 AC: 3005 AN: 1423140 Hom.: 15 Cov.: 31 AF XY: 0.00211 AC XY: 1483 AN XY: 703880

Gnomad4 AFR exome AF: 0.000217

Gnomad4 AMR exome AF: 0.000123

Gnomad4 ASJ exome AF: 0.0000412

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.0153

Gnomad4 NFE exome AF: 0.00197

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00204 AC: 311 AN: 152172 Hom.: 1 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74394

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0143

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00162 Hom.: 0

Bravo AF: 0.000926

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000983 AC: 8

ExAC AF: 0.00305 AC: 364

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	BCR: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Benign	0.0091	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	2.0	M;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.97	N;N
REVEL	Benign	0.15
Sift	Benign	0.072	T;T
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;D
Vest4		0.60
MVP		0.56
MPC		0.73
ClinPred		0.043	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.16
gMVP		0.46

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: rs149933313; hg19: chr22-23523602;