rs374925052

Variant names:

• chr19-47228208-G-A
• rs374925052
• NM_014417.5:c.224C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_014417.5(BBC3):​c.224C>T​(p.Ser75Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,098,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: BBC3 NM_014417.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.103824675).
• BP6: Variant 19-47228208-G-A is Benign according to our data. Variant chr19-47228208-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2508533.Status of the report is criteria_provided_single_submitter, 1 stars.

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.224C>T	p.Ser75Phe	missense	Exon 2 of 4	NP_055232.1	Q9BXH1-1
	BBC3	NM_001127240.3		c.327C>T	p.Phe109Phe	synonymous	Exon 2 of 4	NP_001120712.1	Q96PG8-2
	BBC3	NM_001127241.3		c.89-1454C>T		intron	N/A	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.224C>T	p.Ser75Phe	missense	Exon 2 of 4	ENSP00000395862.2	Q9BXH1-1
	BBC3	ENST00000449228.5	TSL:1	c.327C>T	p.Phe109Phe	synonymous	Exon 2 of 4	ENSP00000404503.1	Q96PG8-2
	BBC3	ENST00000341983.8	TSL:1	c.89-1454C>T		intron	N/A	ENSP00000341155.4	Q9BXH1-2

Frequencies

GnomAD3 genomes AF: 0.00000689 AC: 1 AN: 145126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000221

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000189 AC: 18 AN: 953082 Hom.: 0 Cov.: 32 AF XY: 0.0000157 AC XY: 7 AN XY: 446572

African (AFR) AF: 0.00 AC: 0 AN: 19202

American (AMR) AF: 0.00 AC: 0 AN: 4718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9558

East Asian (EAS) AF: 0.000273 AC: 4 AN: 14634

South Asian (SAS) AF: 0.00 AC: 0 AN: 18346

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2220

European-Non Finnish (NFE) AF: 0.00000595 AC: 5 AN: 840930

Other (OTH) AF: 0.000255 AC: 9 AN: 35296

GnomAD4 genome AF: 0.00000689 AC: 1 AN: 145126 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 70578

African (AFR) AF: 0.00 AC: 0 AN: 40172

American (AMR) AF: 0.00 AC: 0 AN: 14680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3366

East Asian (EAS) AF: 0.000221 AC: 1 AN: 4534

South Asian (SAS) AF: 0.00 AC: 0 AN: 4250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9160

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65750

Other (OTH) AF: 0.00 AC: 0 AN: 2026

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

Asia WGS AF: 0.000290 AC: 1 AN: 3466

ClinVar

ClinVar submissions

Significance: Likely benign

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	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.3
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.015	B
Vest4		0.18
MutPred		0.21		Loss of glycosylation at S75 (P = 0.0039)
MVP		0.62
ClinPred		0.19	T
GERP RS		2.6
Mutation Taster		=99/1	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: rs374925052; hg19: chr19-47731465;