2-60546217-T-G

Position:

• chr2-60546217-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3 PP5

The NM_022893.4(BCL11A):​c.139A>C​(p.Thr47Pro) 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BCL11A NM_022893.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_022893.4
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793
• PP5: Variant 2-60546217-T-G is Pathogenic according to our data. Variant chr2-60546217-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 253300.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-60546217-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL11A	NM_022893.4	c.139A>C	p.Thr47Pro	missense_variant	2/4	ENST00000642384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL11A	ENST00000642384.2	c.139A>C	p.Thr47Pro	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:1

Revision: no assertion criteria provided

Submissions by phenotype

Dias-Logan syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 08, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	32
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.70	.;.;.;.;.;.;.;D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Uncertain	2.6	.;M;M;.;.;.;.;M;M;.;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.3	.;D;D;.;.;.;D;.;D;.;.;.;.;.;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	.;D;D;.;.;.;D;.;D;.;.;.;.;.;.
Sift4G	Uncertain	0.0020	.;D;D;.;.;.;D;.;D;.;.;.;D;.;.
Polyphen		1.0, 1.0	.;.;D;.;.;.;.;D;D;.;.;.;.;.;.
Vest4		0.68, 0.81, 0.66, 0.68, 0.81
MutPred		0.48		Gain of disorder (P = 0.0324);Gain of disorder (P = 0.0324);Gain of disorder (P = 0.0324);.;Gain of disorder (P = 0.0324);.;Gain of disorder (P = 0.0324);Gain of disorder (P = 0.0324);Gain of disorder (P = 0.0324);.;Gain of disorder (P = 0.0324);.;Gain of disorder (P = 0.0324);.;Gain of disorder (P = 0.0324);
MVP		0.71
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.81
gMVP		0.80

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: rs886037864; hg19: chr2-60773352;