22-23181457-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_004327.4(BCR):c.497G>A(p.Gly166Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,607,158 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (12 hom.)
• Consequence: BCR NM_004327.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.05

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005127102).
• BP6: Variant 22-23181457-G-A is Benign according to our data. Variant chr22-23181457-G-A is described in ClinVar as [Benign]. Clinvar id is 720879.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 303 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCR	NM_004327.4	c.497G>A	p.Gly166Asp	missense_variant	1/23	ENST00000305877.13
BCR	NM_021574.3	c.497G>A	p.Gly166Asp	missense_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCR	ENST00000305877.13	c.497G>A	p.Gly166Asp	missense_variant	1/23	1	NM_004327.4	P1
BCR	ENST00000359540.7	c.497G>A	p.Gly166Asp	missense_variant	1/22	1
BCR	ENST00000479188.5	n.129+1625G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 303 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00308 AC: 742 AN: 241220 Hom.: 4 AF XY: 0.00298 AC XY: 394 AN XY: 132352

Gnomad AFR exome AF: 0.000532

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.00408

Gnomad OTH exome AF: 0.00419

GnomAD4 exome AF: 0.00264 AC: 3846 AN: 1454844 Hom.: 12 Cov.: 33 AF XY: 0.00251 AC XY: 1814 AN XY: 722766

Gnomad4 AFR exome AF: 0.000420

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0133

Gnomad4 NFE exome AF: 0.00267

Gnomad4 OTH exome AF: 0.00288

GnomAD4 genome AF: 0.00199 AC: 303 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.00203 AC XY: 151 AN XY: 74476

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0109

Gnomad4 NFE AF: 0.00246

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00232 Hom.: 0

Bravo AF: 0.00118

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00246 AC: 21

ExAC AF: 0.00338 AC: 409

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.94
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.84	N;N
REVEL	Benign	0.030
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.46	T;T
Polyphen		0.36	B;B
Vest4		0.13
MVP		0.41
MPC		0.52
ClinPred		0.030	T
GERP RS		-1.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.089
gMVP		0.24

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: rs148370562; hg19: chr22-23523644;