chr1-85267987-A-G

Variant names:

• chr1-85267987-A-G
• rs77663629
• NM_003921.5:c.347-5T>C

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.001683
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.193
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 475274.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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.347-5T>C		splice_region intron	N/A	NP_003912.1
	BCL10	NM_001320715.2		c.347-38T>C		intron	N/A	NP_001307644.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL10	ENST00000648566.1	MANE Select	c.347-5T>C		splice_region intron	N/A	ENSP00000498104.1
	BCL10	ENST00000620248.3	TSL:5	c.347-38T>C		intron	N/A	ENSP00000480561.2
	BCL10	ENST00000650582.1		n.878-5T>C		splice_region intron	N/A

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

GnomAD2 exomes AF: 0.00214 AC: 417 AN: 194658 AF XY: 0.00158

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 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

African (AFR) AF: 0.0243 AC: 734 AN: 30174

American (AMR) AF: 0.00239 AC: 69 AN: 28840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22268

East Asian (EAS) AF: 0.00 AC: 0 AN: 38158

South Asian (SAS) AF: 0.0000138 AC: 1 AN: 72370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47630

Middle Eastern (MID) AF: 0.000583 AC: 3 AN: 5144

European-Non Finnish (NFE) AF: 0.0000368 AC: 39 AN: 1059082

Other (OTH) AF: 0.00162 AC: 90 AN: 55664

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

African (AFR) AF: 0.0238 AC: 990 AN: 41556

American (AMR) AF: 0.00418 AC: 64 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68032

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00435 Hom.: 1

Bravo AF: 0.00829

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 37 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.1
DANN	Benign	0.79
PhyloP100		0.19
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs77663629; hg19: chr1-85733670;