19-47226720-G-T

Variant names:

• chr19-47226720-G-T
• rs764811014
• NM_014417.5:c.309C>A

Variant summary

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

The NM_014417.5(BBC3):​c.309C>A​(p.His103Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000787 in 1,271,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 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 the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.9e-7 (0 hom.)
• Consequence: BBC3 NM_014417.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.160
• 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]

MIR3190 (HGNC:38190): (microRNA 3190) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR3191 (HGNC:38222): (microRNA 3191) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

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=0.07520309).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014417.5. 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.309C>A	p.His103Gln	missense	Exon 3 of 4	NP_055232.1	Q9BXH1-1
	BBC3	NM_001127240.3		c.412C>A	p.Pro138Thr	missense	Exon 3 of 4	NP_001120712.1	Q96PG8-2
	BBC3	NM_001127241.3		c.123C>A	p.His41Gln	missense	Exon 2 of 3	NP_001120713.1	Q9BXH1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BBC3	ENST00000439096.3	TSL:1 MANE Select	c.309C>A	p.His103Gln	missense	Exon 3 of 4	ENSP00000395862.2	Q9BXH1-1
	BBC3	ENST00000449228.5	TSL:1	c.412C>A	p.Pro138Thr	missense	Exon 3 of 4	ENSP00000404503.1	Q96PG8-2
	BBC3	ENST00000341983.8	TSL:1	c.123C>A	p.His41Gln	missense	Exon 2 of 3	ENSP00000341155.4	Q9BXH1-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.87e-7 AC: 1 AN: 1271430 Hom.: 0 Cov.: 31 AF XY: 0.00000161 AC XY: 1 AN XY: 620054

African (AFR) AF: 0.00 AC: 0 AN: 24638

American (AMR) AF: 0.00 AC: 0 AN: 18042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18606

East Asian (EAS) AF: 0.00 AC: 0 AN: 28544

South Asian (SAS) AF: 0.00 AC: 0 AN: 63234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4434

European-Non Finnish (NFE) AF: 9.76e-7 AC: 1 AN: 1025048

Other (OTH) AF: 0.00 AC: 0 AN: 52444

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.92
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.16
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.12
Sift	Uncertain	0.025	D
Sift4G	Benign	0.66	T
Polyphen		0.0030	B
Vest4		0.17
MutPred		0.088		Loss of loop (P = 0.0804)
MVP		0.31
ClinPred		0.20	T
GERP RS		-0.52
Varity_R		0.49
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: rs764811014; hg19: chr19-47729977;