rs1555376295

Positions:

• chr14-99175639-G-GGGGCT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_138576.4(BCL11B):​c.1192_1196dupAGCCC​(p.Lys400fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCL11B NM_138576.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.41

Genes affected

BCL11B (HGNC:13222): (BCL11 transcription factor B) This gene encodes a C2H2-type zinc finger protein and is closely related to BCL11A, a gene whose translocation may be associated with B-cell malignancies. Although the specific function of this gene has not been determined, the encoded protein is known to be a transcriptional repressor, and is regulated by the NURD nucleosome remodeling and histone deacetylase complex. Four alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-99175639-G-GGGGCT is Pathogenic according to our data. Variant chr14-99175639-G-GGGGCT is described in ClinVar as [Pathogenic]. Clinvar id is 521135.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL11B	NM_138576.4	c.1192_1196dupAGCCC	p.Lys400fs	frameshift_variant	4/4	ENST00000357195.8	NP_612808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCL11B	ENST00000357195.8	c.1192_1196dupAGCCC	p.Lys400fs	frameshift_variant	4/4	1	NM_138576.4	ENSP00000349723.3
BCL11B	ENST00000345514.2	c.979_983dupAGCCC	p.Lys329fs	frameshift_variant	3/3	1		ENSP00000280435.6
BCL11B	ENST00000443726.2	c.610_614dupAGCCC	p.Lys206fs	frameshift_variant	2/2	5		ENSP00000387419.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2018

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555376295; hg19: chr14-99641976;