chr2-60460419-A-C

Position:

• chr2-60460419-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_022893.4(BCL11A):​c.2493T>G​(p.Asp831Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCL11A NM_022893.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

Genes affected

BCL11A (HGNC:13221): (BCL11 transcription factor A) This gene encodes a C2H2 type zinc-finger protein by its similarity to the mouse Bcl11a/Evi9 protein. The corresponding mouse gene is a common site of retroviral integration in myeloid leukemia, and may function as a leukemia disease gene, in part, through its interaction with BCL6. During hematopoietic cell differentiation, this gene is down-regulated. It is possibly involved in lymphoma pathogenesis since translocations associated with B-cell malignancies also deregulates its expression. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BCL11A. . Gene score misZ 3.835 (greater than the threshold 3.09). Trascript score misZ 3.6065 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, Dias-Logan syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.081282824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL11A	NM_022893.4	c.2493T>G	p.Asp831Glu	missense_variant	4/4	ENST00000642384.2	NP_075044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCL11A	ENST00000642384.2	c.2493T>G	p.Asp831Glu	missense_variant	4/4		NM_022893.4	ENSP00000496168

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

The c.2493T>G (p.D831E) alteration is located in exon 4 (coding exon 4) of the BCL11A gene. This alteration results from a T to G substitution at nucleotide position 2493, causing the aspartic acid (D) at amino acid position 831 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	20
DANN	Benign	0.80
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.14	N;.
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Uncertain	0.74	T
REVEL	Benign	0.059
Polyphen		0.0	B;B
MutPred		0.19		Gain of methylation at K833 (P = 0.0812);.;
MVP		0.21
ClinPred		0.068	T
GERP RS		3.8
Varity_R		0.051
gMVP		0.77

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: chr2-60687554;