chr15-79970776-T-C

Position:

• chr15-79970776-T-C

Variant summary

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

The NM_004049.4(BCL2A1):​c.344A>G​(p.Tyr115Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BCL2A1 NM_004049.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.255

Genes affected

BCL2A1 (HGNC:991): (BCL2 related protein A1) This gene encodes a member of the BCL-2 protein family. The proteins of this family form hetero- or homodimers and act as anti- and pro-apoptotic regulators that are involved in a wide variety of cellular activities such as embryonic development, homeostasis and tumorigenesis. The protein encoded by this gene is able to reduce the release of pro-apoptotic cytochrome c from mitochondria and block caspase activation. This gene is a direct transcription target of NF-kappa B in response to inflammatory mediators, and is up-regulated by different extracellular signals, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), CD40, phorbol ester and inflammatory cytokine TNF and IL-1, which suggests a cytoprotective function that is essential for lymphocyte activation as well as cell survival. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL2A1	NM_004049.4	c.344A>G	p.Tyr115Cys	missense_variant	1/2	ENST00000267953.4	NP_004040.1
BCL2A1	NM_001114735.2	c.344A>G	p.Tyr115Cys	missense_variant	1/3		NP_001108207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCL2A1	ENST00000267953.4	c.344A>G	p.Tyr115Cys	missense_variant	1/2	1	NM_004049.4	ENSP00000267953.3
BCL2A1	ENST00000335661.6	c.344A>G	p.Tyr115Cys	missense_variant	1/3	1		ENSP00000335250.6
BCL2A1	ENST00000677151.1	c.344A>G	p.Tyr115Cys	missense_variant	1/1			ENSP00000504466.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461858 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727230

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

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

Aug 14, 2024

The c.344A>G (p.Y115C) alteration is located in exon 1 (coding exon 1) of the BCL2A1 gene. This alteration results from a A to G substitution at nucleotide position 344, causing the tyrosine (Y) at amino acid position 115 to be replaced by a cysteine (C). 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	0.070
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.38
DEOGEN2	Benign	0.031	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.88	L;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.62	N;N
REVEL	Benign	0.041
Sift	Benign	0.15	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.019	B;.
Vest4		0.076
MutPred		0.54		Gain of methylation at K116 (P = 0.0143);Gain of methylation at K116 (P = 0.0143);
MVP		0.26
MPC		0.65
ClinPred		0.086	T
GERP RS		-3.1
Varity_R		0.46
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.47		Position offset: 1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-80263118;