rs1553352926

Variant names:

• chr2-60545969-A-G
• rs1553352926
• NM_022893.4:c.385+2T>C

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PVS1_ModeratePS1PM2PP5_Strong

The NM_022893.4(BCL11A):c.385+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. This is a canonical splice-site variant (loss-of-function). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.32). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BCL11A NM_022893.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9870
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.32
• Publications: 0 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: Illumina, G2P, Ambry Genetics, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		In-frame splice: disease mechanism, limited domain evidence — moderate (PVS1 downgraded to PM); Splice donor variant predicted to cause an in-frame change; loss of function is a known disease mechanism, but domain evidence is limited.
	PS1Same amino acid change as known pathogenic		Splice site has a more-destructive ClinVar pathogenic — strong (PS1); A more pathogenic splice-site variant at the same position has been reported in ClinVar.
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BCL11A NM_022893.4	MANE Select	c.385+2T>C	splice_donorintron	Intron 2 of 3	Prot: NP_075044.2
	BCL11A NM_001405708.1		c.385+2T>C	splice_donorintron	Intron 2 of 4	Prot: NP_001392637.1 UniProt:
	BCL11A NM_001405709.1		c.385+2T>C	splice_donorintron	Intron 3 of 4	Prot: NP_001392638.1 UniProt:

BCL11A NM_022893.4

MANE Select

HGVSc / HGVSpc.385+2T>C

Exon rankIntron 2 of 3

splice_donorintron

Prot: NP_075044.2

BCL11A NM_001405708.1

HGVSc / HGVSpc.385+2T>C

Exon rankIntron 2 of 4

splice_donorintron

Prot: NP_001392637.1UniProt: Q9H165-1

BCL11A NM_001405709.1

HGVSc / HGVSpc.385+2T>C

Exon rankIntron 3 of 4

splice_donorintron

Prot: NP_001392638.1UniProt: Q9H165-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BCL11A ENST00000642384.2	MANE Select	c.385+2T>C	splice_donorintron	Intron 2 of 3	Prot: ENSP00000496168.1 UniProt:
	BCL11A ENST00000335712.11	TSL:1	c.385+2T>C	splice_donorintron	Intron 2 of 2	Prot: ENSP00000338774.7 UniProt:
	BCL11A ENST00000358510.6	TSL:1	c.385+2T>C	splice_donorintron	Intron 2 of 3	Prot: ENSP00000351307.5 UniProt:

BCL11A ENST00000642384.2

MANE Select

HGVSc / HGVSpc.385+2T>C

Exon rankIntron 2 of 3

splice_donorintron

Prot: ENSP00000496168.1UniProt: Q9H165-1

BCL11A ENST00000335712.11

TSL:1

HGVSc / HGVSpc.385+2T>C

Exon rankIntron 2 of 2

splice_donorintron

Prot: ENSP00000338774.7UniProt: Q9H165-6

BCL11A ENST00000358510.6

TSL:1

HGVSc / HGVSpc.385+2T>C

Exon rankIntron 2 of 3

splice_donorintron

Prot: ENSP00000351307.5UniProt: A0A2U3TZJ5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Dias-Logan syndrome (1)
1	-	-	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	33
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.98	D
GPN-Star LLR	N/A	-9.3
GPN-Star score	N/A	9.3
Mutation Taster	N/A	0/100	disease causing (ClinVar)
PhyloP100	Pathogenic	9.3
PromoterAI	N/A	0.12	Neutral

Showing 13 of 13 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.65
DS_DL_spliceai	Pathogenic	0.99	Position offset: 2
Pangolin (max)	Pathogenic	0.80
Pangolin loss	Pathogenic	0.80	Position offset: 2
SpliceAI score (max)	Pathogenic	0.99	Details are displayed if max score is > 0.2

Showing 6 of 6 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1553352926;

hg19: chr2-60773104;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar