3-187728547-A-G

Position:

• chr3-187728547-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000406870.7(BCL6):​c.1356-3T>C variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00165 in 1,599,856 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (16 hom.)
• Consequence: BCL6 ENST00000406870.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001415
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.06

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 3-187728547-A-G is Benign according to our data. Variant chr3-187728547-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 781975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00165 (2385/1447740) while in subpopulation MID AF= 0.0206 (84/4082). AF 95% confidence interval is 0.017. There are 16 homozygotes in gnomad4_exome. There are 1366 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 247 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL6	NM_001706.5	c.1356-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000406870.7	NP_001697.2
LOC100131635	NR_034062.1	n.294-3824A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCL6	ENST00000406870.7	c.1356-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001706.5	ENSP00000384371	P1
	ENST00000449623.5	n.347-4977A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 247 AN: 151998 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00250 AC: 589 AN: 235956 Hom.: 0 AF XY: 0.00290 AC XY: 372 AN XY: 128070

Gnomad AFR exome AF: 0.000460

Gnomad AMR exome AF: 0.00224

Gnomad ASJ exome AF: 0.00959

Gnomad EAS exome AF: 0.0000586

Gnomad SAS exome AF: 0.00642

Gnomad FIN exome AF: 0.0000481

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00165 AC: 2385 AN: 1447740 Hom.: 16 Cov.: 32 AF XY: 0.00190 AC XY: 1366 AN XY: 720354

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.00936

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00649

Gnomad4 FIN exome AF: 0.000189

Gnomad4 NFE exome AF: 0.00107

Gnomad4 OTH exome AF: 0.00293

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152116 Hom.: 2 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74384

Gnomad4 AFR AF: 0.000458

Gnomad4 AMR AF: 0.00308

Gnomad4 ASJ AF: 0.00923

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00664

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00212 Hom.: 1

Bravo AF: 0.00164

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BCL6: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.8
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.022
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: rs113668878; hg19: chr3-187446335;