2-111150070-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138621.5(BCL2L11):c.421G>A(p.Asp141Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BCL2L11 NM_138621.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

Genes affected

BCL2L11 (HGNC:994): (BCL2 like 11) The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The protein encoded by this gene contains a Bcl-2 homology domain 3 (BH3). It has been shown to interact with other members of the BCL-2 protein family and to act as an apoptotic activator. The expression of this gene can be induced by nerve growth factor (NGF), as well as by the forkhead transcription factor FKHR-L1, which suggests a role of this gene in neuronal and lymphocyte apoptosis. Transgenic studies of the mouse counterpart suggested that this gene functions as an essential initiator of apoptosis in thymocyte-negative selection. Several alternatively spliced transcript variants of this gene have been identified. [provided by RefSeq, Jun 2013]

MIR4435-2HG (HGNC:35163): (MIR4435-2 host gene)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19071952).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL2L11	NM_138621.5	c.421G>A	p.Asp141Asn	missense_variant	3/4	ENST00000393256.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL2L11	ENST00000393256.8	c.421G>A	p.Asp141Asn	missense_variant	3/4	1	NM_138621.5	P1
MIR4435-2HG	ENST00000645030.2	n.453-113148C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461662 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2023

The c.421G>A (p.D141N) alteration is located in exon 3 (coding exon 2) of the BCL2L11 gene. This alteration results from a G to A substitution at nucleotide position 421, causing the aspartic acid (D) at amino acid position 141 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Benign	-0.020
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	0.65	D;D;D;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.6	D;.;.;.;.;N;.
REVEL	Benign	0.084
Sift	Uncertain	0.012	D;.;.;.;.;D;.
Sift4G	Uncertain	0.014	D;T;D;T;D;T;.
Polyphen		0.050	B;.;.;.;.;B;.
Vest4		0.48
MVP		0.23
MPC		0.13
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.56
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs2077065300; hg19: chr2-111907647; COSMIC: COSV100427463; COSMIC: COSV100427463;