rs886037865

chr2-60546213-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_022893.4(BCL11A):c.143G>T(p.Cys48Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C48R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BCL11A NM_022893.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a region_of_interest Required for nuclear body formation and for SUMO1 recruitment (size 209) in uniprot entity BC11A_HUMAN there are 13 pathogenic changes around while only 4 benign (76%) in NM_022893.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, BCL11A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 2-60546213-C-A is Pathogenic according to our data. Variant chr2-60546213-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 253301.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-60546213-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL11A	NM_022893.4	c.143G>T	p.Cys48Phe	missense_variant	2/4	ENST00000642384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL11A	ENST00000642384.2	c.143G>T	p.Cys48Phe	missense_variant	2/4		NM_022893.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Dias-Logan syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 08, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Oct 17, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	33
Dann	Benign	0.96
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
Polyphen		1.0, 1.0	.;.;D;.;.;.;.;D;D;.;.;.;.;.;.
Vest4		0.90, 0.96, 0.98, 0.97, 0.96
MutPred		0.93		Loss of disorder (P = 0.1743);Loss of disorder (P = 0.1743);Loss of disorder (P = 0.1743);.;Loss of disorder (P = 0.1743);.;Loss of disorder (P = 0.1743);Loss of disorder (P = 0.1743);Loss of disorder (P = 0.1743);.;Loss of disorder (P = 0.1743);.;Loss of disorder (P = 0.1743);.;Loss of disorder (P = 0.1743);
MVP		0.99
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.92

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: rs886037865; hg19: chr2-60773348;