22-17683257-T-G

Variant summary

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

The NM_015367.4(BCL2L13):c.165T>G(p.Ile55Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. I55V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BCL2L13 NM_015367.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.99

Genes affected

BCL2L13 (HGNC:17164): (BCL2 like 13) This gene encodes a mitochondrially-localized protein with conserved B-cell lymphoma 2 homology motifs. Overexpression of the encoded protein results in apoptosis. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Jul 2012]

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=0.10064533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL2L13	NM_015367.4	c.165T>G	p.Ile55Met	missense_variant	3/7	ENST00000317582.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL2L13	ENST00000317582.10	c.165T>G	p.Ile55Met	missense_variant	3/7	1	NM_015367.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000416 AC: 1 AN: 240260 Hom.: 0 AF XY: 0.00000768 AC XY: 1 AN XY: 130186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000569

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442436 Hom.: 0 Cov.: 28 AF XY: 0.00000139 AC XY: 1 AN XY: 718022

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jul 11, 2023

The c.165T>G (p.I55M) alteration is located in exon 3 (coding exon 2) of the BCL2L13 gene. This alteration results from a T to G substitution at nucleotide position 165, causing the isoleucine (I) at amino acid position 55 to be replaced by a methionine (M). 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	0.084
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	18
Dann	Uncertain	0.98
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.55	N;.;.;.;.;N;N;.
MutationTaster	Benign	1.0	D;D;D;N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.90	N;.;.;.;.;N;N;N
REVEL	Benign	0.035
Sift	Benign	0.057	T;.;.;.;.;D;T;D
Sift4G	Benign	0.080	T;T;T;D;T;T;T;T
Polyphen		0.14	B;.;.;.;.;P;B;P
Vest4		0.021
MutPred		0.16		Gain of ubiquitination at K60 (P = 0.1537);.;Gain of ubiquitination at K60 (P = 0.1537);Gain of ubiquitination at K60 (P = 0.1537);.;Gain of ubiquitination at K60 (P = 0.1537);Gain of ubiquitination at K60 (P = 0.1537);Gain of ubiquitination at K60 (P = 0.1537);
MVP		0.57
MPC		0.21
ClinPred		0.30	T
GERP RS		3.4
Varity_R		0.087
gMVP		0.18

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: rs904669706; hg19: chr22-18166023;