3-187728528-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001706.5(BCL6):c.1372C>T(p.Pro458Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,456,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BCL6 NM_001706.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.07

Genes affected

BCL6 (HGNC:1001): (BCL6 transcription repressor) The protein encoded by this gene is a zinc finger transcription factor and contains an N-terminal POZ domain. This protein acts as a sequence-specific repressor of transcription, and has been shown to modulate the transcription of STAT-dependent IL-4 responses of B cells. This protein can interact with a variety of POZ-containing proteins that function as transcription corepressors. This gene is found to be frequently translocated and hypermutated in diffuse large-cell lymphoma (DLCL), and may be involved in the pathogenesis of DLCL. Alternatively spliced transcript variants encoding different protein isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, BCL6
• BP4: Computational evidence support a benign effect (MetaRNN=0.27107045).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL6	NM_001706.5	c.1372C>T	p.Pro458Ser	missense_variant	6/10	ENST00000406870.7
LOC100131635	NR_034062.1	n.294-3843G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL6	ENST00000406870.7	c.1372C>T	p.Pro458Ser	missense_variant	6/10	1	NM_001706.5	P1
	ENST00000449623.5	n.347-4996G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456976 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 724842

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jan 12, 2024

The c.1372C>T (p.P458S) alteration is located in exon 6 (coding exon 4) of the BCL6 gene. This alteration results from a C to T substitution at nucleotide position 1372, causing the proline (P) at amino acid position 458 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	0.093
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	23
Dann	Uncertain	0.98
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T;.;D;.
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.27	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N;N;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
Sift4G	Benign	0.69	T;T;T;T
Polyphen		1.0	.;D;D;.
Vest4		0.34
MutPred		0.23		Gain of glycosylation at S460 (P = 0.0074);Gain of glycosylation at S460 (P = 0.0074);Gain of glycosylation at S460 (P = 0.0074);Gain of glycosylation at S460 (P = 0.0074);
MVP		0.53
MPC		0.19
ClinPred		0.58	D
GERP RS		5.0
Varity_R		0.11
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-187446316; COSMIC: COSV51654482; COSMIC: COSV51654482;