15-79971064-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004049.4(BCL2A1):​c.56G>A​(p.Cys19Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 1,613,632 control chromosomes in the GnomAD database, including 64,676 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.27 (6014 hom., cov: 33)
  • Exomes 𝑓: 0.28 (58662 hom.)
• Consequence: BCL2A1 NM_004049.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• Publications: 44 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.9030386E-5).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCL2A1	NM_004049.4	c.56G>A	p.Cys19Tyr	missense_variant	Exon 1 of 2	ENST00000267953.4	NP_004040.1
BCL2A1	NM_001114735.2	c.56G>A	p.Cys19Tyr	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>A	p.Cys19Tyr	missense_variant	Exon 1 of 2	1	NM_004049.4	ENSP00000267953.3
BCL2A1	ENST00000335661.6	c.56G>A	p.Cys19Tyr	missense_variant	Exon 1 of 3	1		ENSP00000335250.6
BCL2A1	ENST00000677151.1	c.56G>A	p.Cys19Tyr	missense_variant	Exon 1 of 1			ENSP00000504466.1

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41653 AN: 151968 Hom.: 6011 Cov.: 33

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.550

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.280

GnomAD2 exomes AF: 0.304 AC: 76401 AN: 251292 AF XY: 0.305

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.340

Gnomad ASJ exome AF: 0.226

Gnomad EAS exome AF: 0.561

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.279

GnomAD4 exome AF: 0.275 AC: 402594 AN: 1461546 Hom.: 58662 Cov.: 35 AF XY: 0.279 AC XY: 202575 AN XY: 727090

African (AFR) AF: 0.254 AC: 8486 AN: 33470

American (AMR) AF: 0.330 AC: 14769 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 6017 AN: 26134

East Asian (EAS) AF: 0.527 AC: 20918 AN: 39696

South Asian (SAS) AF: 0.402 AC: 34704 AN: 86246

European-Finnish (FIN) AF: 0.228 AC: 12152 AN: 53414

Middle Eastern (MID) AF: 0.293 AC: 1692 AN: 5766

European-Non Finnish (NFE) AF: 0.258 AC: 286296 AN: 1111720

Other (OTH) AF: 0.291 AC: 17560 AN: 60382

GnomAD4 genome AF: 0.274 AC: 41683 AN: 152086 Hom.: 6014 Cov.: 33 AF XY: 0.277 AC XY: 20611 AN XY: 74336

African (AFR) AF: 0.260 AC: 10786 AN: 41492

American (AMR) AF: 0.280 AC: 4274 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 804 AN: 3472

East Asian (EAS) AF: 0.550 AC: 2846 AN: 5174

South Asian (SAS) AF: 0.416 AC: 2007 AN: 4820

European-Finnish (FIN) AF: 0.234 AC: 2467 AN: 10554

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.257 AC: 17463 AN: 67982

Other (OTH) AF: 0.280 AC: 589 AN: 2106

Alfa AF: 0.263 Hom.: 24681

Bravo AF: 0.278

TwinsUK AF: 0.257 AC: 954

ALSPAC AF: 0.255 AC: 983

ESP6500AA AF: 0.241 AC: 1063

ESP6500EA AF: 0.257 AC: 2210

ExAC AF: 0.303 AC: 36829

Asia WGS AF: 0.433 AC: 1506 AN: 3478

EpiCase AF: 0.254

EpiControl AF: 0.254

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.66
DEOGEN2	Benign	0.051	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.17	T;T
MetaRNN	Benign	0.000059	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.1	N;N
PhyloP100		1.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	2.7	N;N
REVEL	Benign	0.056
Sift	Benign	0.74	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.016
MPC		0.85
ClinPred		0.0066	T
GERP RS		1.9
PromoterAI		-0.012	Neutral
Varity_R		0.071
gMVP		0.49
Mutation Taster		=98/2	polymorphism (auto)

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; COSMIC: COSV51213224;