19-44748942-C-A

Position:

• chr19-44748942-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005178.5(BCL3):​c.152C>A​(p.Ala51Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000369 in 1,084,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: BCL3 NM_005178.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.172

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11948556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL3	NM_005178.5	c.152C>A	p.Ala51Glu	missense_variant	1/9	ENST00000164227.10	NP_005169.2
BCL3	XM_011527198.4	c.152C>A	p.Ala51Glu	missense_variant	1/9		XP_011525500.3
BCL3	XM_017027110.2	c.136+814C>A		intron_variant			XP_016882599.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCL3	ENST00000164227.10	c.152C>A	p.Ala51Glu	missense_variant	1/9	1	NM_005178.5	ENSP00000164227	P1
BCL3	ENST00000487394.1	n.541C>A		non_coding_transcript_exon_variant	2/2	3
BCL3	ENST00000403534.7	n.424+814C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000369 AC: 4 AN: 1084606 Hom.: 0 Cov.: 30 AF XY: 0.00000577 AC XY: 3 AN XY: 520214

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: 0.0000660

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000218

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000622 AC: 2

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

Aug 13, 2021

The c.152C>A (p.A51E) alteration is located in exon 1 (coding exon 1) of the BCL3 gene. This alteration results from a C to A substitution at nucleotide position 152, causing the alanine (A) at amino acid position 51 to be replaced by a glutamic acid (E). 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	Benign	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.012
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.046	D
Polyphen		0.069	B
Vest4		0.15
MutPred		0.33		Gain of helix (P = 0.0034);
MVP		0.57
MPC		0.38
ClinPred		0.23	T
GERP RS		-0.090
Varity_R		0.19
gMVP		0.31

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: rs768745302; hg19: chr19-45252199;