22-23180998-C-G

Position:

• chr22-23180998-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004327.4(BCR):​c.38C>G​(p.Ala13Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000761 in 1,314,374 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: BCR NM_004327.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.71

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCR	NM_004327.4	c.38C>G	p.Ala13Gly	missense_variant	1/23	ENST00000305877.13	NP_004318.3
BCR	NM_021574.3	c.38C>G	p.Ala13Gly	missense_variant	1/22		NP_067585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCR	ENST00000305877.13	c.38C>G	p.Ala13Gly	missense_variant	1/23	1	NM_004327.4	ENSP00000303507	P1
BCR	ENST00000359540.7	c.38C>G	p.Ala13Gly	missense_variant	1/22	1		ENSP00000352535
BCR	ENST00000479188.5	n.129+1166C>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.61e-7 AC: 1 AN: 1314374 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 651694

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000147

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Mar 18, 2024

The c.38C>G (p.A13G) alteration is located in exon 1 (coding exon 1) of the BCR gene. This alteration results from a C to G substitution at nucleotide position 38, causing the alanine (A) at amino acid position 13 to be replaced by a glycine (G). 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	0.45
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		1.0	D;D
Vest4		0.47
MutPred		0.51		Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);
MVP		0.67
MPC		1.0
ClinPred		0.93	D
GERP RS		3.6
Varity_R		0.71
gMVP		0.11

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: rs199561166; hg19: chr22-23523185;