rs77663629

Positions:

• chr1-85267987-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003921.5(BCL10):​c.347-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,511,654 control chromosomes in the GnomAD database, including 24 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0071 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (12 hom.)
• Consequence: BCL10 NM_003921.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001683
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.193

Genes affected

BCL10 (HGNC:989): (BCL10 immune signaling adaptor) This gene was identified by its translocation in a case of mucosa-associated lymphoid tissue (MALT) lymphoma. The protein encoded by this gene contains a caspase recruitment domain (CARD), and has been shown to induce apoptosis and to activate NF-kappaB. This protein is reported to interact with other CARD domain containing proteins including CARD9, 10, 11 and 14, which are thought to function as upstream regulators in NF-kappaB signaling. This protein is found to form a complex with MALT1, a protein encoded by another gene known to be translocated in MALT lymphoma. MALT1 and this protein are thought to synergize in the activation of NF-kappaB, and the deregulation of either of them may contribute to the same pathogenetic process that leads to the malignancy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 1-85267987-A-G is Benign according to our data. Variant chr1-85267987-A-G is described in ClinVar as [Benign]. Clinvar id is 475274.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-85267987-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00708 (1079/152324) while in subpopulation AFR AF= 0.0238 (990/41556). AF 95% confidence interval is 0.0226. There are 12 homozygotes in gnomad4. There are 514 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL10	NM_003921.5	c.347-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000648566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL10	ENST00000648566.1	c.347-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_003921.5	P1
BCL10	ENST00000620248.3	c.347-38T>C		intron_variant		5
BCL10	ENST00000650582.1	n.878-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00710 AC: 1081 AN: 152206 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00214 AC: 417 AN: 194658 Hom.: 4 AF XY: 0.00158 AC XY: 169 AN XY: 106676

Gnomad AFR exome AF: 0.0254

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000721

Gnomad OTH exome AF: 0.000454

GnomAD4 exome AF: 0.000689 AC: 936 AN: 1359330 Hom.: 12 Cov.: 25 AF XY: 0.000621 AC XY: 417 AN XY: 670970

Gnomad4 AFR exome AF: 0.0243

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000138

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000368

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00708 AC: 1079 AN: 152324 Hom.: 12 Cov.: 33 AF XY: 0.00690 AC XY: 514 AN XY: 74498

Gnomad4 AFR AF: 0.0238

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00393 Hom.: 1

Bravo AF: 0.00829

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 37 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.1
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.11		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: rs77663629; hg19: chr1-85733670;