Genetic Variant NM_022893.4:c.198C>A (chr2-60546158-G-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_022893.4(BCL11A):c.198C>A(p.His66Gln) 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

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 10.0

Publications

6 publications found

Variant links:

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: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P

BCL11A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.919

PP5

Variant 2-60546158-G-T is Pathogenic according to our data. Variant chr2-60546158-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 253302.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022893.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BCL11A	NM_022893.4	MANE Select	c.198C>A	p.His66Gln	missense	Exon 2 of 4	NP_075044.2
BCL11A	NM_001405708.1		c.198C>A	p.His66Gln	missense	Exon 2 of 5	NP_001392637.1	D9YZW0
BCL11A	NM_001405709.1		c.198C>A	p.His66Gln	missense	Exon 3 of 5	NP_001392638.1	D9YZW0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BCL11A	ENST00000642384.2	MANE Select	c.198C>A	p.His66Gln	missense	Exon 2 of 4	ENSP00000496168.1	Q9H165-1
BCL11A	ENST00000335712.11	TSL:1	c.198C>A	p.His66Gln	missense	Exon 2 of 3	ENSP00000338774.7	Q9H165-6
BCL11A	ENST00000358510.6	TSL:1	c.198C>A	p.His66Gln	missense	Exon 2 of 4	ENSP00000351307.5	A0A2U3TZJ5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Dias-Logan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.72

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

0.91

MutationAssessor

Uncertain

2.6

PhyloP100

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.83

MutPred

0.70

Gain of disorder (P = 0.0655)

MVP

0.96

ClinPred

0.99

GERP RS

5.8

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.89

gMVP

0.80

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over