rs1000886222

Variant names:

• chr19-44748854-G-A
• rs1000886222
• NM_005178.5:c.64G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005178.5(BCL3):​c.64G>A​(p.Ala22Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000905 in 1,105,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000047 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: BCL3 NM_005178.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.223
• Publications: 0 publications found

Genes affected

BCL3 (HGNC:998): (BCL3 transcription coactivator) This gene is a proto-oncogene candidate. It is identified by its translocation into the immunoglobulin alpha-locus in some cases of B-cell leukemia. The protein encoded by this gene contains seven ankyrin repeats, which are most closely related to those found in I kappa B proteins. This protein functions as a transcriptional co-activator that activates through its association with NF-kappa B homodimers. The expression of this gene can be induced by NF-kappa B, which forms a part of the autoregulatory loop that controls the nuclear residence of p50 NF-kappa B. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.097435296).
• BS2: High AC in GnomAd4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005178.5. 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
	BCL3	NM_005178.5	MANE Select	c.64G>A	p.Ala22Thr	missense	Exon 1 of 9	NP_005169.2	P20749

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL3	ENST00000164227.10	TSL:1 MANE Select	c.64G>A	p.Ala22Thr	missense	Exon 1 of 9	ENSP00000164227.5	P20749
	BCL3	ENST00000487394.1	TSL:3	n.453G>A		non_coding_transcript_exon	Exon 2 of 2
	BCL3	ENST00000403534.7	TSL:2	n.424+726G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000470 AC: 7 AN: 148980 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000466

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000314 AC: 3 AN: 956236 Hom.: 0 Cov.: 30 AF XY: 0.00000444 AC XY: 2 AN XY: 450058

African (AFR) AF: 0.00 AC: 0 AN: 18626

American (AMR) AF: 0.000435 AC: 2 AN: 4602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8954

East Asian (EAS) AF: 0.00 AC: 0 AN: 14066

South Asian (SAS) AF: 0.00 AC: 0 AN: 18498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12682

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2264

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841718

Other (OTH) AF: 0.0000287 AC: 1 AN: 34826

GnomAD4 genome AF: 0.0000470 AC: 7 AN: 148980 Hom.: 0 Cov.: 30 AF XY: 0.0000275 AC XY: 2 AN XY: 72602

African (AFR) AF: 0.00 AC: 0 AN: 41046

American (AMR) AF: 0.000466 AC: 7 AN: 15008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66842

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000793

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.22
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.021
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.038	D
Polyphen		0.0010	B
Vest4		0.073
MutPred		0.28		Gain of phosphorylation at A22 (P = 0.0085)
MVP		0.60
MPC		0.15
ClinPred		0.13	T
GERP RS		1.0
PromoterAI		-0.12	Neutral
Varity_R		0.079
gMVP		0.27
Mutation Taster		=100/0	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: rs1000886222; hg19: chr19-45252111;