NM_003921.5:c.13G>T

Variant names:

• chr1-85276340-C-A
• rs12037217
• NM_003921.5:c.13G>T

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.13G>T​(p.Ala5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,613,546 control chromosomes in the GnomAD database, including 780 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (93 hom., cov: 34)
  • Exomes 𝑓: 0.025 (687 hom.)
• Consequence: BCL10 NM_003921.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.77
• Publications: 22 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-AS1 (HGNC:55868): (BCL10 antisense RNA 1)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015875101).
• BP6: Variant 1-85276340-C-A is Benign according to our data. Variant chr1-85276340-C-A is described in ClinVar as Benign. ClinVar VariationId is 475271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.106 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL10	NM_003921.5	MANE Select	c.13G>T	p.Ala5Ser	missense	Exon 1 of 3	NP_003912.1
	BCL10	NM_001320715.2		c.13G>T	p.Ala5Ser	missense	Exon 1 of 3	NP_001307644.1
	BCL10-AS1	NR_045484.1		n.-18C>A		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL10	ENST00000648566.1	MANE Select	c.13G>T	p.Ala5Ser	missense	Exon 1 of 3	ENSP00000498104.1
	BCL10	ENST00000620248.3	TSL:5	c.13G>T	p.Ala5Ser	missense	Exon 1 of 3	ENSP00000480561.2
	BCL10	ENST00000649060.1		n.13G>T		non_coding_transcript_exon	Exon 1 of 2	ENSP00000497490.1

Frequencies

GnomAD3 genomes AF: 0.0232 AC: 3529 AN: 152104 Hom.: 94 Cov.: 34

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0283

Gnomad ASJ AF: 0.0933

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0247

Gnomad OTH AF: 0.0369

GnomAD2 exomes AF: 0.0300 AC: 7512 AN: 250084 AF XY: 0.0304

Gnomad AFR exome AF: 0.00413

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0878

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.00453

Gnomad NFE exome AF: 0.0250

Gnomad OTH exome AF: 0.0349

GnomAD4 exome AF: 0.0247 AC: 36149 AN: 1461324 Hom.: 687 Cov.: 35 AF XY: 0.0251 AC XY: 18212 AN XY: 726974

African (AFR) AF: 0.00523 AC: 175 AN: 33460

American (AMR) AF: 0.0199 AC: 891 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0910 AC: 2377 AN: 26110

East Asian (EAS) AF: 0.0837 AC: 3320 AN: 39680

South Asian (SAS) AF: 0.0199 AC: 1719 AN: 86210

European-Finnish (FIN) AF: 0.00551 AC: 294 AN: 53396

Middle Eastern (MID) AF: 0.0643 AC: 370 AN: 5754

European-Non Finnish (NFE) AF: 0.0226 AC: 25108 AN: 1111654

Other (OTH) AF: 0.0314 AC: 1895 AN: 60374

GnomAD4 genome AF: 0.0232 AC: 3525 AN: 152222 Hom.: 93 Cov.: 34 AF XY: 0.0227 AC XY: 1689 AN XY: 74440

African (AFR) AF: 0.00467 AC: 194 AN: 41542

American (AMR) AF: 0.0283 AC: 433 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0933 AC: 324 AN: 3472

East Asian (EAS) AF: 0.114 AC: 587 AN: 5162

South Asian (SAS) AF: 0.0212 AC: 102 AN: 4822

European-Finnish (FIN) AF: 0.00452 AC: 48 AN: 10614

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0247 AC: 1680 AN: 67988

Other (OTH) AF: 0.0389 AC: 82 AN: 2110

Alfa AF: 0.0301 Hom.: 175

Bravo AF: 0.0255

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0197 AC: 76

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0284 AC: 244

ExAC AF: 0.0289 AC: 3508

Asia WGS AF: 0.0720 AC: 250 AN: 3478

EpiCase AF: 0.0318

EpiControl AF: 0.0331

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	BCL10-related disorder (1)
-	-	1	Immunodeficiency 37 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.039
Sift	Uncertain	0.025	D
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.056
MPC		0.72
ClinPred		0.016	T
GERP RS		3.2
PromoterAI		-0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.49
Mutation Taster		=99/1	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: rs12037217; hg19: chr1-85742023; COSMIC: COSV65354093; COSMIC: COSV65354093;