rs3768235

Variant names:

• chr1-85267691-C-T
• rs3768235
• NM_003921.5:c.638G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003921.5(BCL10):​c.638G>A​(p.Gly213Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0591 in 1,613,906 control chromosomes in the GnomAD database, including 3,401 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (250 hom., cov: 33)
  • Exomes 𝑓: 0.060 (3151 hom.)
• Consequence: BCL10 NM_003921.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.257
• Publications: 32 publications found

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]

BCL10 Gene-Disease associations (from GenCC):

• immunodeficiency 37

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011563003).
• BP6: Variant 1-85267691-C-T is Benign according to our data. Variant chr1-85267691-C-T is described in ClinVar as Benign. ClinVar VariationId is 402410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003921.5. 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
	BCL10	NM_003921.5	MANE Select	c.638G>A	p.Gly213Glu	missense	Exon 3 of 3	NP_003912.1	O95999
	BCL10	NM_001320715.2		c.605G>A	p.Gly202Glu	missense	Exon 3 of 3	NP_001307644.1	A0A087WWW9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL10	ENST00000648566.1	MANE Select	c.638G>A	p.Gly213Glu	missense	Exon 3 of 3	ENSP00000498104.1	O95999
	BCL10	ENST00000913809.1		c.635G>A	p.Gly212Glu	missense	Exon 3 of 3	ENSP00000583868.1
	BCL10	ENST00000620248.3	TSL:5	c.605G>A	p.Gly202Glu	missense	Exon 3 of 3	ENSP00000480561.2	A0A087WWW9

Frequencies

GnomAD3 genomes AF: 0.0473 AC: 7199 AN: 152162 Hom.: 251 Cov.: 33

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0606

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.0899

Gnomad FIN AF: 0.0463

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0550

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0651 AC: 16344 AN: 251142 AF XY: 0.0660

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.0799

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.152

Gnomad FIN exome AF: 0.0461

Gnomad NFE exome AF: 0.0543

Gnomad OTH exome AF: 0.0586

GnomAD4 exome AF: 0.0603 AC: 88113 AN: 1461626 Hom.: 3151 Cov.: 31 AF XY: 0.0610 AC XY: 44361 AN XY: 727126

African (AFR) AF: 0.00989 AC: 331 AN: 33466

American (AMR) AF: 0.0751 AC: 3357 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 671 AN: 26126

East Asian (EAS) AF: 0.157 AC: 6229 AN: 39684

South Asian (SAS) AF: 0.0888 AC: 7660 AN: 86218

European-Finnish (FIN) AF: 0.0475 AC: 2538 AN: 53414

Middle Eastern (MID) AF: 0.0609 AC: 351 AN: 5762

European-Non Finnish (NFE) AF: 0.0569 AC: 63221 AN: 1111892

Other (OTH) AF: 0.0622 AC: 3755 AN: 60376

GnomAD4 genome AF: 0.0473 AC: 7199 AN: 152280 Hom.: 250 Cov.: 33 AF XY: 0.0474 AC XY: 3530 AN XY: 74460

African (AFR) AF: 0.0129 AC: 535 AN: 41564

American (AMR) AF: 0.0608 AC: 930 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 88 AN: 3470

East Asian (EAS) AF: 0.153 AC: 792 AN: 5182

South Asian (SAS) AF: 0.0896 AC: 432 AN: 4824

European-Finnish (FIN) AF: 0.0463 AC: 490 AN: 10592

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0550 AC: 3744 AN: 68034

Other (OTH) AF: 0.0421 AC: 89 AN: 2114

Alfa AF: 0.0504 Hom.: 109

Bravo AF: 0.0466

TwinsUK AF: 0.0558 AC: 207

ALSPAC AF: 0.0651 AC: 251

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.0566 AC: 487

ExAC AF: 0.0639 AC: 7761

Asia WGS AF: 0.141 AC: 488 AN: 3478

EpiCase AF: 0.0523

EpiControl AF: 0.0519

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 37 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.0	N
PhyloP100		0.26
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.057
Sift	Benign	0.37	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.058
MPC		1.0
ClinPred		0.0061	T
GERP RS		-0.91
Varity_R		0.11
gMVP		0.35
Mutation Taster		=97/3	polymorphism (auto)

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: rs3768235; hg19: chr1-85733374; COSMIC: COSV65353501; COSMIC: COSV65353501;