chr14-99174183-C-T

Position:

• chr14-99174183-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_138576.4(BCL11B):​c.2653G>A​(p.Asp885Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BCL11B NM_138576.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.22

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3286966).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL11B	NM_138576.4	c.2653G>A	p.Asp885Asn	missense_variant	4/4	ENST00000357195.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL11B	ENST00000357195.8	c.2653G>A	p.Asp885Asn	missense_variant	4/4	1	NM_138576.4	A2
BCL11B	ENST00000345514.2	c.2440G>A	p.Asp814Asn	missense_variant	3/3	1		P4
BCL11B	ENST00000443726.2	c.2071G>A	p.Asp691Asn	missense_variant	2/2	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461246 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726962

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 11, 2020	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BCL11B-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 885 of the BCL11B protein (p.Asp885Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	BCL11B: PM2, PP2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.77	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.28
MutPred		0.36		Gain of MoRF binding (P = 0.0568);.;.;
MVP		0.44
MPC		1.6
ClinPred		0.95	D
GERP RS		4.9
Varity_R		0.20
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-99640520; COSMIC: COSV61734563;