19-47226594-C-A

Variant names:

• chr19-47226594-C-A
• rs916949219
• ENST00000449228.5:c.538G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001127240.3(BBC3):​c.538G>T​(p.Gly180*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BBC3 NM_001127240.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.788
• Publications: 0 publications found

Genes affected

BBC3 (HGNC:17868): (BCL2 binding component 3) This gene encodes a member of the BCL-2 family of proteins. This family member belongs to the BH3-only pro-apoptotic subclass. The protein cooperates with direct activator proteins to induce mitochondrial outer membrane permeabilization and apoptosis. It can bind to anti-apoptotic Bcl-2 family members to induce mitochondrial dysfunction and caspase activation. Because of its pro-apoptotic role, this gene is a potential drug target for cancer therapy and for tissue injury. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127240.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBC3	NM_014417.5	MANE Select	c.435G>T	p.Ala145Ala	synonymous	Exon 3 of 4	NP_055232.1	Q9BXH1-1
	BBC3	NM_001127240.3		c.538G>T	p.Gly180*	stop_gained	Exon 3 of 4	NP_001120712.1	Q96PG8-2
	BBC3	NM_001127241.3		c.249G>T	p.Ala83Ala	synonymous	Exon 2 of 3	NP_001120713.1	Q9BXH1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBC3	ENST00000449228.5	TSL:1	c.538G>T	p.Gly180*	stop_gained	Exon 3 of 4	ENSP00000404503.1	Q96PG8-2
	BBC3	ENST00000439096.3	TSL:1 MANE Select	c.435G>T	p.Ala145Ala	synonymous	Exon 3 of 4	ENSP00000395862.2	Q9BXH1-1
	BBC3	ENST00000341983.8	TSL:1	c.249G>T	p.Ala83Ala	synonymous	Exon 2 of 3	ENSP00000341155.4	Q9BXH1-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429358 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 709576

African (AFR) AF: 0.00 AC: 0 AN: 30510

American (AMR) AF: 0.00 AC: 0 AN: 41814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25062

East Asian (EAS) AF: 0.00 AC: 0 AN: 36196

South Asian (SAS) AF: 0.00 AC: 0 AN: 82582

European-Finnish (FIN) AF: 0.0000199 AC: 1 AN: 50212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098320

Other (OTH) AF: 0.00 AC: 0 AN: 59002

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.72	D
PhyloP100		-0.79
Vest4		0.81
GERP RS		-0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=142/58	polymorphism

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: rs916949219; hg19: chr19-47729851;