rs1138358

Variant names:

• chr15-79971003-A-C
• rs1138358
• NM_004049.4:c.117T>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 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 0.37 (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
• Publications: 36 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=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 rank	MANE	Protein	UniProt
BCL2A1	NM_004049.4	c.117T>G	p.Asn39Lys	missense_variant	Exon 1 of 2	ENST00000267953.4	NP_004040.1
BCL2A1	NM_001114735.2	c.117T>G	p.Asn39Lys	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.117T>G	p.Asn39Lys	missense_variant	Exon 1 of 2	1	NM_004049.4	ENSP00000267953.3
BCL2A1	ENST00000335661.6	c.117T>G	p.Asn39Lys	missense_variant	Exon 1 of 3	1		ENSP00000335250.6
BCL2A1	ENST00000677151.1	c.117T>G	p.Asn39Lys	missense_variant	Exon 1 of 1			ENSP00000504466.1

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

GnomAD2 exomes AF: 0.332 AC: 83539 AN: 251372 AF XY: 0.327

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 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

African (AFR) AF: 0.602 AC: 20135 AN: 33472

American (AMR) AF: 0.357 AC: 15961 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 6496 AN: 26136

East Asian (EAS) AF: 0.527 AC: 20919 AN: 39698

South Asian (SAS) AF: 0.404 AC: 34861 AN: 86258

European-Finnish (FIN) AF: 0.228 AC: 12156 AN: 53418

Middle Eastern (MID) AF: 0.338 AC: 1952 AN: 5768

European-Non Finnish (NFE) AF: 0.260 AC: 289443 AN: 1111830

Other (OTH) AF: 0.319 AC: 19266 AN: 60392

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

African (AFR) AF: 0.590 AC: 24466 AN: 41456

American (AMR) AF: 0.325 AC: 4962 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 868 AN: 3468

East Asian (EAS) AF: 0.551 AC: 2851 AN: 5176

South Asian (SAS) AF: 0.418 AC: 2016 AN: 4828

European-Finnish (FIN) AF: 0.234 AC: 2472 AN: 10580

Middle Eastern (MID) AF: 0.312 AC: 91 AN: 292

European-Non Finnish (NFE) AF: 0.260 AC: 17707 AN: 67984

Other (OTH) AF: 0.358 AC: 752 AN: 2102

Alfa AF: 0.292 Hom.: 28502

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
PhyloP100		-3.7
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
PromoterAI		0.0070	Neutral
Varity_R		0.18
gMVP		0.26
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: rs1138358; hg19: chr15-80263345; COSMIC: COSV51213210;