chr2-60546213-C-A

Variant names:

• chr2-60546213-C-A
• rs886037865
• NM_022893.4:c.143G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 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
• Publications: 5 publications found

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]

BCL11A Gene-Disease associations (from GenCC):

• Dias-Logan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Ambry Genetics, G2P, Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 10 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
• 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 VariationId is 253301.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCL11A	NM_022893.4	c.143G>T	p.Cys48Phe	missense_variant	Exon 2 of 4	ENST00000642384.2	NP_075044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCL11A	ENST00000642384.2	c.143G>T	p.Cys48Phe	missense_variant	Exon 2 of 4		NM_022893.4	ENSP00000496168.1

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

Sep 08, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 17, 2022

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DEOGEN2	Uncertain	0.74	.;.;.;.;.;.;.;D;.;.;.;.;.;.;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
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	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
MutationAssessor	Uncertain	2.6	.;M;M;.;.;.;.;M;M;.;.;.;M;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.3	.;D;D;.;.;.;D;.;D;.;.;.;.;.;.
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D;D;.;.;.;D;.;D;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;D;D;.;.;.;D;.;D;.;.;.;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
PromoterAI		0.035	Neutral
Varity_R		0.94
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886037865; hg19: chr2-60773348;