22-23181169-A-T

Variant names:

• chr22-23181169-A-T
• rs770716239
• NM_004327.4:c.209A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004327.4(BCR):​c.209A>T​(p.Tyr70Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000317 in 1,260,400 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y70C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: BCR NM_004327.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.209A>T	p.Tyr70Phe	missense	Exon 1 of 23	NP_004318.3
	BCR	NM_021574.3		c.209A>T	p.Tyr70Phe	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.209A>T	p.Tyr70Phe	missense	Exon 1 of 23	ENSP00000303507.8	P11274-1
	BCR	ENST00000359540.7	TSL:1	c.209A>T	p.Tyr70Phe	missense	Exon 1 of 22	ENSP00000352535.3	P11274-2
	BCR	ENST00000928588.1		c.209A>T	p.Tyr70Phe	missense	Exon 1 of 23	ENSP00000598647.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000317 AC: 4 AN: 1260400 Hom.: 0 Cov.: 30 AF XY: 0.00000484 AC XY: 3 AN XY: 620040

African (AFR) AF: 0.00 AC: 0 AN: 26834

American (AMR) AF: 0.00 AC: 0 AN: 26882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20646

East Asian (EAS) AF: 0.00 AC: 0 AN: 28426

South Asian (SAS) AF: 0.00 AC: 0 AN: 63402

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5052

European-Non Finnish (NFE) AF: 0.00000402 AC: 4 AN: 995492

Other (OTH) AF: 0.00 AC: 0 AN: 49832

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.74		Loss of phosphorylation at Y70 (P = 0.0398)
MVP		0.59
MPC		0.62
ClinPred		0.88	D
GERP RS		3.8
Varity_R		0.43
gMVP		0.13
Mutation Taster		=63/37	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: rs770716239; hg19: chr22-23523356;