rs3994992

Variant names:

• chr14-99213170-C-T
• rs3994992
• NM_138576.4:c.640+18175G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138576.4(BCL11B):​c.640+18175G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.318 in 152,042 control chromosomes in the GnomAD database, including 9,204 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (9204 hom., cov: 31)
• Consequence: BCL11B NM_138576.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.946
• Publications: 2 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)

LOC124903412 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

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.640+18175G>A		intron	N/A	NP_612808.1	Q9C0K0-1
	BCL11B	NM_001282237.2		c.637+18175G>A		intron	N/A	NP_001269166.1
	BCL11B	NM_022898.3		c.428-36975G>A		intron	N/A	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.640+18175G>A		intron	N/A	ENSP00000349723.3	Q9C0K0-1
	BCL11B	ENST00000345514.2	TSL:1	c.428-36975G>A		intron	N/A	ENSP00000280435.6	Q9C0K0-2
	BCL11B	ENST00000443726.2	TSL:5	c.59-36975G>A		intron	N/A	ENSP00000387419.2	D3YTK1

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48325 AN: 151922 Hom.: 9211 Cov.: 31

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.0412

Gnomad SAS AF: 0.170

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.437

Gnomad OTH AF: 0.340

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.318 AC: 48326 AN: 152042 Hom.: 9204 Cov.: 31 AF XY: 0.312 AC XY: 23206 AN XY: 74330

African (AFR) AF: 0.139 AC: 5764 AN: 41520

American (AMR) AF: 0.343 AC: 5243 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1276 AN: 3462

East Asian (EAS) AF: 0.0415 AC: 214 AN: 5152

South Asian (SAS) AF: 0.171 AC: 825 AN: 4818

European-Finnish (FIN) AF: 0.387 AC: 4092 AN: 10578

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.437 AC: 29677 AN: 67924

Other (OTH) AF: 0.339 AC: 716 AN: 2114

Alfa AF: 0.397 Hom.: 48617

Bravo AF: 0.306

Asia WGS AF: 0.120 AC: 419 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.9
DANN	Benign	0.59
PhyloP100		0.95
Mutation Taster		=100/0	polymorphism (auto)

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: rs3994992; hg19: chr14-99679507;