chr19-44748924-C-A

Variant names:

• chr19-44748924-C-A
• rs932958438
• NM_005178.5:c.134C>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.134C>A​(p.Ala45Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 1,180,918 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A45V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: BCL3 NM_005178.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71
• 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=0.15435731).
• BS2: High AC in GnomAd4 at 10 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.134C>A	p.Ala45Asp	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.134C>A	p.Ala45Asp	missense	Exon 1 of 9	ENSP00000164227.5	P20749
	BCL3	ENST00000487394.1	TSL:3	n.523C>A		non_coding_transcript_exon	Exon 2 of 2
	BCL3	ENST00000403534.7	TSL:2	n.424+796C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000667 AC: 10 AN: 149822 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000582 AC: 6 AN: 1031096 Hom.: 0 Cov.: 30 AF XY: 0.00000408 AC XY: 2 AN XY: 489708

African (AFR) AF: 0.000193 AC: 4 AN: 20708

American (AMR) AF: 0.00 AC: 0 AN: 7166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11886

East Asian (EAS) AF: 0.00 AC: 0 AN: 20720

South Asian (SAS) AF: 0.00 AC: 0 AN: 21634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2610

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 888646

Other (OTH) AF: 0.0000508 AC: 2 AN: 39384

GnomAD4 genome AF: 0.0000667 AC: 10 AN: 149822 Hom.: 0 Cov.: 31 AF XY: 0.0000274 AC XY: 2 AN XY: 73072

African (AFR) AF: 0.000243 AC: 10 AN: 41130

American (AMR) AF: 0.00 AC: 0 AN: 15080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67300

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.00 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	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.090	N
REVEL	Benign	0.057
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.0020	B
Vest4		0.28
MutPred		0.30		Gain of relative solvent accessibility (P = 0.005)
MVP		0.69
MPC		0.30
ClinPred		0.30	T
GERP RS		1.2
PromoterAI		-0.027	Neutral
Varity_R		0.20
gMVP		0.35
Mutation Taster		=97/3	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: rs932958438; hg19: chr19-45252181;