14-99174415-G-C

Position:

• chr14-99174415-G-C

Variant summary

Our verdict is Pathogenic. Variant got 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 560174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-99174415-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL11B	NM_138576.4	c.2421C>G	p.Asn807Lys	missense_variant	4/4	ENST00000357195.8	NP_612808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCL11B	ENST00000357195.8	c.2421C>G	p.Asn807Lys	missense_variant	4/4	1	NM_138576.4	ENSP00000349723.3
BCL11B	ENST00000345514.2	c.2208C>G	p.Asn736Lys	missense_variant	3/3	1		ENSP00000280435.6
BCL11B	ENST00000443726.2	c.1839C>G	p.Asn613Lys	missense_variant	2/2	5		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

Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 29, 2020	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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 17, 2019	- -

Immunodeficiency 49 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 28, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 07, 2020

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 v4.3

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;T;T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	0.11	N;.;.
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs888230251; hg19: chr14-99640752;