Genetic Variant NM_004049.4:c.56G>A (chr15-79971064-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.38

Publications

44 publications found

Variant links:

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]

BCL2A1 links:

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ACMG classification

Classification was made for transcript

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 link	c.56G>A	p.Cys19Tyr	missense_variant	Exon 1 of 2	ENST00000267953.4	NP_004040.1	Q16548-1
BCL2A1	NM_001114735.2 link	c.56G>A	p.Cys19Tyr	missense_variant	Exon 1 of 3		NP_001108207.1	Q16548-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BCL2A1	ENST00000267953.4 link	c.56G>A	p.Cys19Tyr	missense_variant	Exon 1 of 2	1	NM_004049.4	ENSP00000267953.3	Q16548-1
BCL2A1	ENST00000335661.6 link	c.56G>A	p.Cys19Tyr	missense_variant	Exon 1 of 3	1		ENSP00000335250.6	Q16548-2
BCL2A1	ENST00000677151.1 link	c.56G>A	p.Cys19Tyr	missense_variant	Exon 1 of 1			ENSP00000504466.1	B4E1X9

Frequencies

GnomAD3 genomes

AF:

0.274

AC:

41653

AN:

151968

Hom.:

6011

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.279

AC XY:

202575

AN XY:

727090

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

16487

32974

49462

65949

82436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9988

19976

29964

39952

49940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.274

AC:

41683

AN:

152086

Hom.:

6014

Cov.:

AF XY:

0.277

AC XY:

20611

AN XY:

74336

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.257

AC:

17463

AN:

67982

Other (OTH)

AF:

0.280

AC:

589

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1573

3146

4718

6291

7864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

448

896

1344

1792

2240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.2

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.051

T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.17

T;T

MetaRNN

Benign

0.000059

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-2.1

N;N

PhyloP100

1.4

PrimateAI

Benign

0.29

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

GERP RS

1.9

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.071

gMVP

0.49

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over