chr19-44751346-G-T

Variant names:

• chr19-44751346-G-T
• rs140257795
• NM_005178.5:c.376G>T

Variant summary

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

The NM_005178.5(BCL3):​c.376G>T​(p.Ala126Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,994 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A126T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BCL3 NM_005178.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.86
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.376G>T	p.Ala126Ser	missense	Exon 2 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.376G>T	p.Ala126Ser	missense	Exon 2 of 9	ENSP00000164227.5	P20749
	BCL3	ENST00000444487.1	TSL:5	c.25G>T	p.Ala9Ser	missense	Exon 1 of 8	ENSP00000393731.1	H7C0A2
	BCL3	ENST00000403534.7	TSL:2	n.544G>T		non_coding_transcript_exon	Exon 2 of 8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448994 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 721038

African (AFR) AF: 0.00 AC: 0 AN: 32582

American (AMR) AF: 0.00 AC: 0 AN: 40988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25632

East Asian (EAS) AF: 0.00 AC: 0 AN: 38832

South Asian (SAS) AF: 0.00 AC: 0 AN: 84478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107670

Other (OTH) AF: 0.00 AC: 0 AN: 59796

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.97	L
PhyloP100		2.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.23
Sift	Benign	0.21	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.43
MutPred		0.69		Gain of loop (P = 0.0013)
MVP		0.66
MPC		0.15
ClinPred		0.79	D
GERP RS		5.2
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.22
Mutation Taster		=89/11	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: rs140257795; hg19: chr19-45254603;