rs1555376234

Variant names:

• chr14-99175341-C-A
• rs1555376234
• NM_138576.4:c.1495G>T

Your query was ambiguous. Multiple possible variants found:

• chr14-99175341-C-A
• chr14-99175341-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_138576.4(BCL11B):​c.1495G>T​(p.Glu499*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: BCL11B NM_138576.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.24
• 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, ClinGen, G2P
• immunodeficiency 49

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 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 44 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-99175341-C-A is Pathogenic according to our data. Variant chr14-99175341-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 560178.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL11B	NM_138576.4	MANE Select	c.1495G>T	p.Glu499*	stop_gained	Exon 4 of 4	NP_612808.1	Q9C0K0-1
	BCL11B	NM_001282237.2		c.1492G>T	p.Glu498*	stop_gained	Exon 4 of 4	NP_001269166.1
	BCL11B	NM_022898.3		c.1282G>T	p.Glu428*	stop_gained	Exon 3 of 3	NP_075049.1	Q9C0K0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL11B	ENST00000357195.8	TSL:1 MANE Select	c.1495G>T	p.Glu499*	stop_gained	Exon 4 of 4	ENSP00000349723.3	Q9C0K0-1
	BCL11B	ENST00000345514.2	TSL:1	c.1282G>T	p.Glu428*	stop_gained	Exon 3 of 3	ENSP00000280435.6	Q9C0K0-2
	BCL11B	ENST00000443726.2	TSL:5	c.913G>T	p.Glu305*	stop_gained	Exon 2 of 2	ENSP00000387419.2	D3YTK1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1404414 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 695366

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31674

American (AMR) AF: 0.00 AC: 0 AN: 38252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 37054

South Asian (SAS) AF: 0.00 AC: 0 AN: 81684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4536

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1088496

Other (OTH) AF: 0.00 AC: 0 AN: 58242

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.2
Vest4		0.93
GERP RS		3.6
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1555376234; hg19: chr14-99641678;