NM_004049.4:c.56G>C

Variant names:

• chr15-79971064-C-G
• rs1138357
• NM_004049.4:c.56G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004049.4(BCL2A1):​c.56G>C​(p.Cys19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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)
• Consequence: BCL2A1 NM_004049.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056230992).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCL2A1	NM_004049.4	c.56G>C	p.Cys19Ser	missense_variant	Exon 1 of 2	ENST00000267953.4	NP_004040.1
BCL2A1	NM_001114735.2	c.56G>C	p.Cys19Ser	missense_variant	Exon 1 of 3		NP_001108207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCL2A1	ENST00000267953.4	c.56G>C	p.Cys19Ser	missense_variant	Exon 1 of 2	1	NM_004049.4	ENSP00000267953.3
BCL2A1	ENST00000335661.6	c.56G>C	p.Cys19Ser	missense_variant	Exon 1 of 3	1		ENSP00000335250.6
BCL2A1	ENST00000677151.1	c.56G>C	p.Cys19Ser	missense_variant	Exon 1 of 1			ENSP00000504466.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.48
DEOGEN2	Benign	0.051	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		1.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.89	N;N
REVEL	Benign	0.063
Sift	Benign	0.41	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0	B;.
Vest4		0.074
MutPred		0.46		Gain of disorder (P = 0.0091);Gain of disorder (P = 0.0091);
MVP		0.10
MPC		0.62
ClinPred		0.027	T
GERP RS		1.9
PromoterAI		0.010	Neutral
Varity_R		0.15
gMVP		0.45

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

Other links and lift over

dbSNP: rs1138357; hg19: chr15-80263406;