14-99174415-G-C

Variant names:

• chr14-99174415-G-C
• rs888230251
• NM_138576.4:c.2421C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_138576.4(BCL11B):​c.2421C>G​(p.Asn807Lys) variant causes a missense 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCL11B NM_138576.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.73
• Publications: 5 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-99174415-G-C is Pathogenic according to our data. Variant chr14-99174415-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 560174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL11B	NM_138576.4	MANE Select	c.2421C>G	p.Asn807Lys	missense	Exon 4 of 4	NP_612808.1
	BCL11B	NM_001282237.2		c.2418C>G	p.Asn806Lys	missense	Exon 4 of 4	NP_001269166.1
	BCL11B	NM_022898.3		c.2208C>G	p.Asn736Lys	missense	Exon 3 of 3	NP_075049.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL11B	ENST00000357195.8	TSL:1 MANE Select	c.2421C>G	p.Asn807Lys	missense	Exon 4 of 4	ENSP00000349723.3
	BCL11B	ENST00000345514.2	TSL:1	c.2208C>G	p.Asn736Lys	missense	Exon 3 of 3	ENSP00000280435.6
	BCL11B	ENST00000443726.2	TSL:5	c.1839C>G	p.Asn613Lys	missense	Exon 2 of 2	ENSP00000387419.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities Pathogenic:3

Jun 10, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 17, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 29, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Glu879Asp variant in BCL11B was identified by our study in 1 individual with intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities (PMID: 29985992). Trio genome analysis showed this variant to be de novo in 1 individual. This variant was absent from large population studies. The p.Asn807Lys variant is located in a region of BCL11B that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 29985992). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS2, PM2, PM1_supporting (Richards 2015).

Immunodeficiency 49 Pathogenic:1

Aug 28, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Apr 07, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The N807K variant in the BCL11B gene has been reported previously as a de novo variant in a child with developmental delay, dysmorphic facial features, dental anomalies, feeding anomalies, and low T-cell receptor excision circle (TREC) analysis at birth (Lessel et al., 2018). The variant is not observed in large population cohorts (Lek et al., 2016). The N807K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret N807K as a pathogenic variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.042	T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.11	N
PhyloP100		7.7
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.42		Gain of methylation at N807 (P = 9e-04)
MVP		0.64
MPC		1.5
ClinPred		0.99	D
GERP RS		3.7
Varity_R		0.79
gMVP		0.87
Mutation Taster		=9/91	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: rs888230251; hg19: chr14-99640752;