22-23181098-G-T

Position:

• chr22-23181098-G-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.138G>T​(p.Glu46Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,511,382 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (5 hom.)
• Consequence: BCR NM_004327.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.21

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010390997).
• BP6: Variant 22-23181098-G-T is Benign according to our data. Variant chr22-23181098-G-T is described in ClinVar as [Benign]. Clinvar id is 779478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 238 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCR	NM_004327.4	c.138G>T	p.Glu46Asp	missense_variant	1/23	ENST00000305877.13	NP_004318.3
BCR	NM_021574.3	c.138G>T	p.Glu46Asp	missense_variant	1/22		NP_067585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCR	ENST00000305877.13	c.138G>T	p.Glu46Asp	missense_variant	1/23	1	NM_004327.4	ENSP00000303507	P1
BCR	ENST00000359540.7	c.138G>T	p.Glu46Asp	missense_variant	1/22	1		ENSP00000352535
BCR	ENST00000479188.5	n.129+1266G>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 238 AN: 149400 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000199

Gnomad ASJ AF: 0.000291

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00233

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00293

Gnomad OTH AF: 0.00146

GnomAD3 exomes AF: 0.00170 AC: 294 AN: 173022 Hom.: 0 AF XY: 0.00183 AC XY: 172 AN XY: 93906

Gnomad AFR exome AF: 0.000453

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.000121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000405

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00148 AC: 2017 AN: 1361874 Hom.: 5 Cov.: 30 AF XY: 0.00158 AC XY: 1066 AN XY: 675446

Gnomad4 AFR exome AF: 0.000274

Gnomad4 AMR exome AF: 0.000609

Gnomad4 ASJ exome AF: 0.000130

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000562

Gnomad4 FIN exome AF: 0.00330

Gnomad4 NFE exome AF: 0.00161

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00159 AC: 238 AN: 149508 Hom.: 1 Cov.: 32 AF XY: 0.00152 AC XY: 111 AN XY: 72938

Gnomad4 AFR AF: 0.000218

Gnomad4 AMR AF: 0.000199

Gnomad4 ASJ AF: 0.000291

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00233

Gnomad4 NFE AF: 0.00293

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.00229 Hom.: 1

Bravo AF: 0.00123

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00280 AC: 24

ExAC AF: 0.00142 AC: 170

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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		0.99	D;D
Vest4		0.38
MutPred		0.69		Gain of MoRF binding (P = 0.1349);Gain of MoRF binding (P = 0.1349);
MVP		0.62
MPC		0.70
ClinPred		0.012	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.84
gMVP		0.25

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: rs138513724; hg19: chr22-23523285;