ENST00000358510.6:c.2353C>G

Variant names:

• chr2-60452594-G-C
• rs1265922527
• ENST00000358510.6:c.2353C>G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The ENST00000358510.6(BCL11A):​c.2353C>G​(p.Arg785Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R785P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: BCL11A ENST00000358510.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

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 Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in the BCL11A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 3.835 (above the threshold of 3.09). Trascript score misZ: 3.2296 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 40, Dias-Logan syndrome.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCL11A	NM_001405710.1	c.2455C>G	p.Arg819Gly	missense_variant	Exon 5 of 5		NP_001392639.1
BCL11A	NM_001363864.1	c.2353C>G	p.Arg785Gly	missense_variant	Exon 4 of 4		NP_001350793.1
BCL11A	NM_001405716.1	c.2299C>G	p.Arg767Gly	missense_variant	Exon 5 of 5		NP_001392645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCL11A	ENST00000358510.6	c.2353C>G	p.Arg785Gly	missense_variant	Exon 4 of 4	1		ENSP00000351307.5
BCL11A	ENST00000356842.9	c.2303C>G	p.Ser768Trp	missense_variant	Exon 5 of 5	1		ENSP00000349300.4
BCL11A	ENST00000359629.10	c.703C>G	p.Arg235Gly	missense_variant	Exon 5 of 5	1		ENSP00000352648.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461708 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dias-Logan syndrome Uncertain:1

Jan 15, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.65	.;T;T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.50	T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
PROVEAN	Benign	0.16	.;N;.;.;.;.
REVEL	Benign	0.13
Sift	Uncertain	0.018	.;D;.;.;.;.
Sift4G	Uncertain	0.054	.;T;.;.;.;.
Polyphen		0.24	.;B;.;.;.;.
Vest4		0.28
MutPred		0.33		.;.;.;.;.;Loss of solvent accessibility (P = 0.0159);
MVP		0.52
ClinPred		0.66	D
GERP RS		5.9

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1265922527; hg19: chr2-60679729;