19-48956261-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_138761.4(BAX):c.297G>C(p.Met99Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000125 in 1,438,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.000013 (0 hom.)
• Consequence: BAX NM_138761.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.26

Genes affected

BAX (HGNC:959): (BCL2 associated X, apoptosis regulator) The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. The association and the ratio of BAX to BCL2 also determines survival or death of a cell following an apoptotic stimulus. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis. Multiple alternatively spliced transcript variants, which encode different isoforms, have been reported for this gene. [provided by RefSeq, Dec 2019]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24669823).
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAX	NM_138761.4	c.297G>C	p.Met99Ile	missense_variant	4/6	ENST00000345358.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAX	ENST00000345358.12	c.297G>C	p.Met99Ile	missense_variant	4/6	1	NM_138761.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000217 AC: 5 AN: 230096 Hom.: 0 AF XY: 0.0000239 AC XY: 3 AN XY: 125284

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000376

Gnomad OTH exome AF: 0.000186

GnomAD4 exome AF: 0.0000125 AC: 18 AN: 1438112 Hom.: 0 Cov.: 31 AF XY: 0.0000140 AC XY: 10 AN XY: 715272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.0000842

GnomAD4 genome Cov.: 31

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.297G>C (p.M99I) alteration is located in exon 4 (coding exon 4) of the BAX gene. This alteration results from a G to C substitution at nucleotide position 297, causing the methionine (M) at amino acid position 99 to be replaced by an isoleucine (I). 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	0.90
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	20
Dann	Benign	0.76
DEOGEN2	Benign	0.12	T;T;.;.;T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.25	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.57	N;.;N;.;.;N
MutationTaster	Benign	0.88	D;D;D;D;D;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	0.38	N;.;N;N;.;N
REVEL	Benign	0.17
Sift	Benign	0.96	T;.;T;T;.;T
Sift4G	Benign	0.94	T;T;T;T;T;T
Polyphen		0.064	B;.;B;B;.;B
Vest4		0.39
MutPred		0.69		Loss of catalytic residue at V95 (P = 0.02);.;Loss of catalytic residue at V95 (P = 0.02);.;.;Loss of catalytic residue at V95 (P = 0.02);
MVP		0.34
MPC		0.23
ClinPred		0.10	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.56

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: rs775579234; hg19: chr19-49459518;