NM_138576.4:c.2449_2456dupAGCCACAC

Variant names:

• chr14-99174379-G-GGTGTGGCT
• rs1555376035
• NM_138576.4:c.2449_2456dupAGCCACAC

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.58
• Publications: 1 publications found

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, G2P
• immunodeficiency 49

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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 id is 560175.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCL11B	NM_138576.4	c.2449_2456dupAGCCACAC	p.Gly820AlafsTer27	frameshift_variant	Exon 4 of 4	ENST00000357195.8	NP_612808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCL11B	ENST00000357195.8	c.2449_2456dupAGCCACAC	p.Gly820AlafsTer27	frameshift_variant	Exon 4 of 4	1	NM_138576.4	ENSP00000349723.3
BCL11B	ENST00000345514.2	c.2236_2243dupAGCCACAC	p.Gly749AlafsTer27	frameshift_variant	Exon 3 of 3	1		ENSP00000280435.6
BCL11B	ENST00000443726.2	c.1867_1874dupAGCCACAC	p.Gly626AlafsTer27	frameshift_variant	Exon 2 of 2	5		ENSP00000387419.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities Pathogenic:1

Aug 29, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555376035; hg19: chr14-99640716;