3-187729913-C-A

Position:

• chr3-187729913-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001706.5(BCL6):​c.492G>T​(p.Glu164Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,614,044 control chromosomes in the GnomAD database, including 761 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.023 (39 hom., cov: 32)
  • Exomes 𝑓: 0.030 (722 hom.)
• Consequence: BCL6 NM_001706.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.13

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003096044).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0232 (3540/152278) while in subpopulation NFE AF= 0.0331 (2253/68024). AF 95% confidence interval is 0.032. There are 39 homozygotes in gnomad4. There are 1644 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 3540 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL6	NM_001706.5	c.492G>T	p.Glu164Asp	missense_variant	5/10	ENST00000406870.7	NP_001697.2
LOC100131635	NR_034062.1	n.294-2458C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCL6	ENST00000406870.7	c.492G>T	p.Glu164Asp	missense_variant	5/10	1	NM_001706.5	ENSP00000384371	P1
	ENST00000449623.5	n.347-3611C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0233 AC: 3542 AN: 152160 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.00712

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.0453

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0245

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0349

GnomAD3 exomes AF: 0.0221 AC: 5552 AN: 251196 Hom.: 80 AF XY: 0.0223 AC XY: 3025 AN XY: 135738

Gnomad AFR exome AF: 0.00665

Gnomad AMR exome AF: 0.0156

Gnomad ASJ exome AF: 0.0452

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00615

Gnomad FIN exome AF: 0.0246

Gnomad NFE exome AF: 0.0314

Gnomad OTH exome AF: 0.0267

GnomAD4 exome AF: 0.0295 AC: 43138 AN: 1461766 Hom.: 722 Cov.: 35 AF XY: 0.0289 AC XY: 21002 AN XY: 727172

Gnomad4 AFR exome AF: 0.00568

Gnomad4 AMR exome AF: 0.0172

Gnomad4 ASJ exome AF: 0.0488

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00613

Gnomad4 FIN exome AF: 0.0251

Gnomad4 NFE exome AF: 0.0333

Gnomad4 OTH exome AF: 0.0308

GnomAD4 genome AF: 0.0232 AC: 3540 AN: 152278 Hom.: 39 Cov.: 32 AF XY: 0.0221 AC XY: 1644 AN XY: 74448

Gnomad4 AFR AF: 0.00710

Gnomad4 AMR AF: 0.0270

Gnomad4 ASJ AF: 0.0453

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.0245

Gnomad4 NFE AF: 0.0331

Gnomad4 OTH AF: 0.0345

Alfa AF: 0.0294 Hom.: 42

Bravo AF: 0.0235

TwinsUK AF: 0.0372 AC: 138

ALSPAC AF: 0.0340 AC: 131

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0331 AC: 285

ExAC AF: 0.0206 AC: 2504

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0328

EpiControl AF: 0.0338

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;T;T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.72	T;.;T;.
MetaRNN	Benign	0.0031	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;L;L;L
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.63	.;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.28	.;T;T;T
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.0070	.;B;B;.
Vest4		0.076
MutPred		0.11		Loss of glycosylation at P168 (P = 0.1164);Loss of glycosylation at P168 (P = 0.1164);Loss of glycosylation at P168 (P = 0.1164);Loss of glycosylation at P168 (P = 0.1164);
MPC		0.16
ClinPred		0.010	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.14

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: rs61752081; hg19: chr3-187447701; COSMIC: COSV51652125; COSMIC: COSV51652125;