22-23181304-C-A

Variant names:

• chr22-23181304-C-A
• rs746637123
• NM_004327.4:c.344C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004327.4(BCR):​c.344C>A​(p.Ala115Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000827 in 1,208,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. A115V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: BCR NM_004327.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10093564).

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.344C>A	p.Ala115Asp	missense	Exon 1 of 23	NP_004318.3
	BCR	NM_021574.3		c.344C>A	p.Ala115Asp	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.344C>A	p.Ala115Asp	missense	Exon 1 of 23	ENSP00000303507.8	P11274-1
	BCR	ENST00000359540.7	TSL:1	c.344C>A	p.Ala115Asp	missense	Exon 1 of 22	ENSP00000352535.3	P11274-2
	BCR	ENST00000928588.1		c.344C>A	p.Ala115Asp	missense	Exon 1 of 23	ENSP00000598647.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.27e-7 AC: 1 AN: 1208540 Hom.: 0 Cov.: 30 AF XY: 0.00000170 AC XY: 1 AN XY: 588626

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23904

American (AMR) AF: 0.00 AC: 0 AN: 13204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17530

East Asian (EAS) AF: 0.00 AC: 0 AN: 27144

South Asian (SAS) AF: 0.00 AC: 0 AN: 50802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3638

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 987322

Other (OTH) AF: 0.00 AC: 0 AN: 48686

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.040
Sift	Benign	0.097	T
Sift4G	Uncertain	0.059	T
Polyphen		0.0050	B
Vest4		0.14
MutPred		0.14		Gain of solvent accessibility (P = 0.0648)
MVP		0.28
MPC		0.59
ClinPred		0.078	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.13
gMVP		0.32
Mutation Taster		=83/17	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: rs746637123; hg19: chr22-23523491;