19-47221723-C-A

Variant names:

• chr19-47221723-C-A
• rs1277941099
• ENST00000449228.5:c.764G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001127240.3(BBC3):​c.764G>T​(p.Gly255Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BBC3 NM_001127240.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.552

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40726703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BBC3	NM_014417.5	c.*79G>T		3_prime_UTR_variant	Exon 4 of 4	ENST00000439096.3	NP_055232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BBC3	ENST00000439096	c.*79G>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_014417.5	ENSP00000395862.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.764G>T (p.G255V) alteration is located in exon 4 (coding exon 4) of the BBC3 gene. This alteration results from a G to T substitution at nucleotide position 764, causing the glycine (G) at amino acid position 255 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.41	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.57
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.055	T;D
Vest4		0.68
MVP		0.70
MPC		0.027
ClinPred		0.80	D
GERP RS		2.2
Varity_R		0.39
gMVP		0.049

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: rs1277941099; hg19: chr19-47724980;