Genetic Variant BCL11B:p.Gly820AlafsTer27 (chr14-99174379-G-GGTGTGGCT) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_138576.4(BCL11B):c.2449_2456dupAGCCACAC(p.Gly820AlafsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T819T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

BCL11B
NM_138576.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.58

Publications

1 publications found

Variant links:

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]

BCL11B Gene-Disease associations (from GenCC):

intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, ClinGen, G2P
immunodeficiency 49
Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

BCL11B links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 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 15 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-99174379-G-GGTGTGGCT is Pathogenic according to our data. Variant chr14-99174379-G-GGTGTGGCT is described in ClinVar as Pathogenic. ClinVar VariationId is 560175.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138576.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BCL11B	NM_138576.4	MANE Select	c.2449_2456dupAGCCACAC	p.Gly820AlafsTer27	frameshift	Exon 4 of 4	NP_612808.1	Q9C0K0-1
BCL11B	NM_001282237.2		c.2446_2453dupAGCCACAC	p.Gly819AlafsTer27	frameshift	Exon 4 of 4	NP_001269166.1
BCL11B	NM_022898.3		c.2236_2243dupAGCCACAC	p.Gly749AlafsTer27	frameshift	Exon 3 of 3	NP_075049.1	Q9C0K0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BCL11B	ENST00000357195.8	TSL:1 MANE Select	c.2449_2456dupAGCCACAC	p.Gly820AlafsTer27	frameshift	Exon 4 of 4	ENSP00000349723.3	Q9C0K0-1
BCL11B	ENST00000345514.2	TSL:1	c.2236_2243dupAGCCACAC	p.Gly749AlafsTer27	frameshift	Exon 3 of 3	ENSP00000280435.6	Q9C0K0-2
BCL11B	ENST00000443726.2	TSL:5	c.1867_1874dupAGCCACAC	p.Gly626AlafsTer27	frameshift	Exon 2 of 2	ENSP00000387419.2	D3YTK1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.6

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over