Genetic Variant ENST00000449228.5:c.229C>T (chr19-47228306-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000449228.5(BBC3):c.229C>T(p.Arg77Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,223,456 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: 𝑓 0.000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000047 ( 0 hom. )

Consequence

BBC3
ENST00000449228.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.876

Publications

0 publications found

Variant links:

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]

BBC3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0776588).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000449228.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BBC3	NM_014417.5	MANE Select	c.126C>T	p.Pro42Pro	synonymous	Exon 2 of 4	NP_055232.1	Q9BXH1-1
BBC3	NM_001127240.3		c.229C>T	p.Arg77Trp	missense	Exon 2 of 4	NP_001120712.1	Q96PG8-2
BBC3	NM_001127241.3		c.89-1552C>T		intron	N/A	NP_001120713.1	Q9BXH1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BBC3	ENST00000449228.5	TSL:1	c.229C>T	p.Arg77Trp	missense	Exon 2 of 4	ENSP00000404503.1	Q96PG8-2
BBC3	ENST00000439096.3	TSL:1 MANE Select	c.126C>T	p.Pro42Pro	synonymous	Exon 2 of 4	ENSP00000395862.2	Q9BXH1-1
BBC3	ENST00000341983.8	TSL:1	c.89-1552C>T		intron	N/A	ENSP00000341155.4	Q9BXH1-2

Frequencies

GnomAD3 genomes

AF:

0.0000791

AC:

AN:

151774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000722

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD4 exome

AF:

0.00000467

AC:

AN:

1071682

Hom.:

Cov.:

AF XY:

0.00000395

AC XY:

AN XY:

506216

show subpopulations

African (AFR)

AF:

0.0000444

AC:

AN:

22528

American (AMR)

AF:

0.000371

AC:

AN:

8080

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13920

East Asian (EAS)

AF:

0.00

AC:

AN:

25832

South Asian (SAS)

AF:

0.00

AC:

AN:

19448

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2874

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

915016

Other (OTH)

AF:

0.0000233

AC:

AN:

42970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000791

AC:

AN:

151774

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41364

American (AMR)

AF:

0.000722

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67864

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000166

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.29

CADD

Benign

7.4

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.27

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.63

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.078

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

-0.88

PROVEAN

Benign

-1.8

REVEL

Benign

0.039

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.031

Vest4

0.18

MutPred

0.28

Loss of methylation at R77 (P = 0.0317)

MVP

0.29

MPC

1.4

ClinPred

0.20

GERP RS

-4.9

Varity_R

0.16

gMVP

0.14

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over