chr19-47226686-G-A

Variant names:

• chr19-47226686-G-A
• rs761068549
• ENST00000449228.5:c.446C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127240.3(BBC3):​c.446C>T​(p.Ser149Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,344,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000074 (0 hom.)
• Consequence: BBC3 NM_001127240.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13235795).

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.343C>T	p.Leu115Leu	synonymous	Exon 3 of 4	NP_055232.1	Q9BXH1-1
	BBC3	NM_001127240.3		c.446C>T	p.Ser149Phe	missense	Exon 3 of 4	NP_001120712.1	Q96PG8-2
	BBC3	NM_001127241.3		c.157C>T	p.Leu53Leu	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.446C>T	p.Ser149Phe	missense	Exon 3 of 4	ENSP00000404503.1	Q96PG8-2
	BBC3	ENST00000439096.3	TSL:1 MANE Select	c.343C>T	p.Leu115Leu	synonymous	Exon 3 of 4	ENSP00000395862.2	Q9BXH1-1
	BBC3	ENST00000341983.8	TSL:1	c.157C>T	p.Leu53Leu	synonymous	Exon 2 of 3	ENSP00000341155.4	Q9BXH1-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000108 AC: 1 AN: 92232 AF XY: 0.0000195

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000744 AC: 10 AN: 1344598 Hom.: 0 Cov.: 31 AF XY: 0.00000756 AC XY: 5 AN XY: 661230

African (AFR) AF: 0.00 AC: 0 AN: 27448

American (AMR) AF: 0.00 AC: 0 AN: 28362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22202

East Asian (EAS) AF: 0.00 AC: 0 AN: 32518

South Asian (SAS) AF: 0.000122 AC: 9 AN: 73662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4730

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1056952

Other (OTH) AF: 0.0000180 AC: 1 AN: 55612

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000107 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.8
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.051
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.60	T
Vest4		0.14
MutPred		0.22		Loss of glycosylation at S149 (P = 0.0023)
MVP		0.63
MPC		1.4
ClinPred		0.35	T
GERP RS		-0.94
Varity_R		0.36
gMVP		0.032
Mutation Taster		=100/0	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: rs761068549; hg19: chr19-47729943;