rs1138358

Positions:

• chr15-79971003-A-C
• chr15-79971003-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004049.4(BCL2A1):​c.117T>G​(p.Asn39Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,613,772 control chromosomes in the GnomAD database, including 77,971 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.37 (12248 hom., cov: 33)
  • Exomes 𝑓: 0.29 (65723 hom.)
• Consequence: BCL2A1 NM_004049.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.67

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.0458941E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.584 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL2A1	NM_004049.4	c.117T>G	p.Asn39Lys	missense_variant	1/2	ENST00000267953.4	NP_004040.1
BCL2A1	NM_001114735.2	c.117T>G	p.Asn39Lys	missense_variant	1/3		NP_001108207.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCL2A1	ENST00000267953.4	c.117T>G	p.Asn39Lys	missense_variant	1/2	1	NM_004049.4	ENSP00000267953	P1
BCL2A1	ENST00000335661.6	c.117T>G	p.Asn39Lys	missense_variant	1/3	1		ENSP00000335250
BCL2A1	ENST00000677151.1	c.117T>G	p.Asn39Lys	missense_variant	1/1			ENSP00000504466

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56485 AN: 151958 Hom.: 12217 Cov.: 33

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.414

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.359

GnomAD3 exomes AF: 0.332 AC: 83539 AN: 251372 Hom.: 15684 AF XY: 0.327 AC XY: 44362 AN XY: 135858

Gnomad AFR exome AF: 0.589

Gnomad AMR exome AF: 0.363

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.561

Gnomad SAS exome AF: 0.407

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.299

GnomAD4 exome AF: 0.288 AC: 421189 AN: 1461696 Hom.: 65723 Cov.: 36 AF XY: 0.290 AC XY: 210915 AN XY: 727154

Gnomad4 AFR exome AF: 0.602

Gnomad4 AMR exome AF: 0.357

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.527

Gnomad4 SAS exome AF: 0.404

Gnomad4 FIN exome AF: 0.228

Gnomad4 NFE exome AF: 0.260

Gnomad4 OTH exome AF: 0.319

GnomAD4 genome AF: 0.372 AC: 56562 AN: 152076 Hom.: 12248 Cov.: 33 AF XY: 0.373 AC XY: 27711 AN XY: 74350

Gnomad4 AFR AF: 0.590

Gnomad4 AMR AF: 0.325

Gnomad4 ASJ AF: 0.250

Gnomad4 EAS AF: 0.551

Gnomad4 SAS AF: 0.418

Gnomad4 FIN AF: 0.234

Gnomad4 NFE AF: 0.260

Gnomad4 OTH AF: 0.358

Alfa AF: 0.281 Hom.: 13882

Bravo AF: 0.391

TwinsUK AF: 0.261 AC: 967

ALSPAC AF: 0.258 AC: 995

ESP6500AA AF: 0.561 AC: 2472

ESP6500EA AF: 0.261 AC: 2248

ExAC AF: 0.337 AC: 40860

Asia WGS AF: 0.456 AC: 1585 AN: 3478

EpiCase AF: 0.259

EpiControl AF: 0.260

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0010
DANN	Benign	0.32
DEOGEN2	Benign	0.025	T;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.26	T;T
MetaRNN	Benign	0.000020	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.38	N;N
REVEL	Benign	0.031
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.018
MutPred		0.21		Gain of MoRF binding (P = 0.0228);Gain of MoRF binding (P = 0.0228);
MPC		0.58
ClinPred		0.018	T
GERP RS		-10
Varity_R		0.18
gMVP		0.26

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: rs1138358; hg19: chr15-80263345; COSMIC: COSV51213210;