19-44748989-C-T

Variant names:

• chr19-44748989-C-T
• rs1360246384
• NM_005178.5:c.199C>T

Variant summary

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

The NM_005178.5(BCL3):​c.199C>T​(p.Pro67Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000812 in 1,232,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 8.1e-7 (0 hom.)
• Consequence: BCL3 NM_005178.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.382

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=0.10715559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCL3	NM_005178.5	c.199C>T	p.Pro67Ser	missense_variant	Exon 1 of 9	ENST00000164227.10	NP_005169.2
BCL3	XM_011527198.4	c.199C>T	p.Pro67Ser	missense_variant	Exon 1 of 9		XP_011525500.3
BCL3	XM_017027110.2	c.136+861C>T		intron_variant	Intron 1 of 6		XP_016882599.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCL3	ENST00000164227.10	c.199C>T	p.Pro67Ser	missense_variant	Exon 1 of 9	1	NM_005178.5	ENSP00000164227.5
BCL3	ENST00000487394.1	n.588C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3
BCL3	ENST00000403534.7	n.424+861C>T		intron_variant	Intron 1 of 7	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.12e-7 AC: 1 AN: 1232126 Hom.: 0 Cov.: 30 AF XY: 0.00000165 AC XY: 1 AN XY: 605140

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000100

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.199C>T (p.P67S) alteration is located in exon 1 (coding exon 1) of the BCL3 gene. This alteration results from a C to T substitution at nucleotide position 199, causing the proline (P) at amino acid position 67 to be replaced by a serine (S). 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	0.088
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.026
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.28	T
Polyphen		0.0050	B
Vest4		0.094
MutPred		0.20		Loss of catalytic residue at P67 (P = 0.0492);
MVP		0.46
MPC		0.18
ClinPred		0.18	T
GERP RS		0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.32

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: rs1360246384; hg19: chr19-45252246;