2-60460724-G-T

Position:

• chr2-60460724-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_022893.4(BCL11A):​c.2188C>A​(p.Pro730Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,802 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: 0.0000021 (0 hom.)
• Consequence: BCL11A NM_022893.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.75

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 2 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=0.36614776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL11A	NM_022893.4	c.2188C>A	p.Pro730Thr	missense_variant	4/4	ENST00000642384.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL11A	ENST00000642384.2	c.2188C>A	p.Pro730Thr	missense_variant	4/4		NM_022893.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251130 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135782

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461802 Hom.: 0 Cov.: 39 AF XY: 0.00000275 AC XY: 2 AN XY: 727198

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dias-Logan syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.2188C>A(p.Pro730Thr) variant in BCL11A gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Pro730Thr variant has been reported with allele frequency of 0.0008% ing gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid change p.Pro730Thr in BCL11A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 730 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 30, 2022	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2023

The c.2188C>A (p.P730T) alteration is located in exon 4 (coding exon 4) of the BCL11A gene. This alteration results from a C to A substitution at nucleotide position 2188, causing the proline (P) at amino acid position 730 to be replaced by a threonine (T). 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	0.24
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	.;.;D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-3.3	D;D;.;.
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;T;.;.
Sift4G	Uncertain	0.0090	D;T;.;.
Polyphen		0.90, 1.0	.;.;P;D
Vest4		0.49
MutPred		0.20		Gain of phosphorylation at P730 (P = 0.0051);.;Gain of phosphorylation at P730 (P = 0.0051);.;
MVP		0.53
ClinPred		0.85	D
GERP RS		5.9
Varity_R		0.20
gMVP		0.69

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: rs775970880; hg19: chr2-60687859;