rs750610248

Variant names:

• chr14-99175513-A-C
• rs750610248
• NM_138576.4:c.1323T>G

Your query was ambiguous. Multiple possible variants found:

• chr14-99175513-A-C
• chr14-99175513-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_138576.4(BCL11B):​c.1323T>G​(p.Asn441Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N441I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCL11B NM_138576.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.983
• Publications: 19 publications found

Genes affected

BCL11B (HGNC:13222): (BCL11 transcription factor B) This gene encodes a C2H2-type zinc finger protein and is closely related to BCL11A, a gene whose translocation may be associated with B-cell malignancies. Although the specific function of this gene has not been determined, the encoded protein is known to be a transcriptional repressor, and is regulated by the NURD nucleosome remodeling and histone deacetylase complex. Four alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Aug 2013]

BCL11B Gene-Disease associations (from GenCC):

• intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, G2P
• immunodeficiency 49

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751
• PP5: Variant 14-99175513-A-C is Pathogenic according to our data. Variant chr14-99175513-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 254673.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCL11B	NM_138576.4	c.1323T>G	p.Asn441Lys	missense_variant	Exon 4 of 4	ENST00000357195.8	NP_612808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCL11B	ENST00000357195.8	c.1323T>G	p.Asn441Lys	missense_variant	Exon 4 of 4	1	NM_138576.4	ENSP00000349723.3
BCL11B	ENST00000345514.2	c.1110T>G	p.Asn370Lys	missense_variant	Exon 3 of 3	1		ENSP00000280435.6
BCL11B	ENST00000443726.2	c.741T>G	p.Asn247Lys	missense_variant	Exon 2 of 2	5		ENSP00000387419.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Immunodeficiency 49 Pathogenic:1

Aug 28, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Combined immunodeficiency Pathogenic:1

Mar 01, 2016

Puck Laboratory, University of California, San Francisco

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.
PhyloP100		0.98
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;P;.
Vest4		0.78
MutPred		0.57		Gain of methylation at N441 (P = 0.0121);.;.;
MVP		0.76
MPC		2.7
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.81
gMVP		0.92
Mutation Taster		=5/95	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: rs750610248; hg19: chr14-99641850;