1-85267644-T-C

Variant names:

• chr1-85267644-T-C
• rs780769969
• NM_003921.5:c.685A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003921.5(BCL10):​c.685A>G​(p.Thr229Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T229S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BCL10 NM_003921.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.53
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061416715).

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.685A>G	p.Thr229Ala	missense	Exon 3 of 3	NP_003912.1	O95999
	BCL10	NM_001320715.2		c.652A>G	p.Thr218Ala	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.685A>G	p.Thr229Ala	missense	Exon 3 of 3	ENSP00000498104.1	O95999
	BCL10	ENST00000913809.1		c.682A>G	p.Thr228Ala	missense	Exon 3 of 3	ENSP00000583868.1
	BCL10	ENST00000620248.3	TSL:5	c.652A>G	p.Thr218Ala	missense	Exon 3 of 3	ENSP00000480561.2	A0A087WWW9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.72
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.69	N
PhyloP100		2.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.15
Sift	Benign	0.46	T
Sift4G	Benign	0.082	T
Polyphen		0.0	B
Vest4		0.010
MutPred		0.084		Loss of phosphorylation at T229 (P = 0.0071)
MVP		0.60
MPC		0.77
ClinPred		0.57	D
GERP RS		2.1
Varity_R		0.068
gMVP		0.16
Mutation Taster		=92/8	polymorphism

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: rs780769969; hg19: chr1-85733327;