NM_138761.4:c.114G>T

Variant names:

• chr19-48955714-G-T
• rs141306106
• NM_138761.4:c.114G>T

Variant summary

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

The NM_138761.4(BAX):​c.114G>T​(p.Met38Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000511 in 1,606,202 control chromosomes in the GnomAD database, with no homozygous occurrence. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: BAX NM_138761.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.473
• Publications: 4 publications found

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]

BAX Gene-Disease associations (from GenCC):

• leukemia, acute lymphocytic, susceptibility to, 1

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000305635 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138761.4. 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
	BAX	NM_138761.4	MANE Select	c.114G>T	p.Met38Ile	missense	Exon 3 of 6	NP_620116.1	Q07812-1
	BAX	NM_001291429.2		c.3G>T	p.Met1?	start_lost	Exon 2 of 4	NP_001278358.1
	BAX	NM_001291428.2		c.114G>T	p.Met38Ile	missense	Exon 3 of 6	NP_001278357.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAX	ENST00000345358.12	TSL:1 MANE Select	c.114G>T	p.Met38Ile	missense	Exon 3 of 6	ENSP00000263262.9	Q07812-1
	BAX	ENST00000293288.12	TSL:1	c.114G>T	p.Met38Ile	missense	Exon 3 of 5	ENSP00000293288.8	Q07812-2
	BAX	ENST00000415969.6	TSL:1	c.114G>T	p.Met38Ile	missense	Exon 3 of 6	ENSP00000389971.2	Q07812-8

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151710 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.0000375 AC: 9 AN: 240068 AF XY: 0.0000461

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000307

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.0000543 AC: 79 AN: 1454492 Hom.: 0 Cov.: 30 AF XY: 0.0000498 AC XY: 36 AN XY: 723238

African (AFR) AF: 0.00 AC: 0 AN: 33250

American (AMR) AF: 0.0000457 AC: 2 AN: 43808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25768

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39460

South Asian (SAS) AF: 0.0000586 AC: 5 AN: 85366

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53136

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5728

European-Non Finnish (NFE) AF: 0.0000587 AC: 65 AN: 1107932

Other (OTH) AF: 0.0000500 AC: 3 AN: 60044

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151710 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74088

African (AFR) AF: 0.00 AC: 0 AN: 41270

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67910

Other (OTH) AF: 0.000481 AC: 1 AN: 2078

Alfa AF: 0.0000364 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.18
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.84
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.68	D
M_CAP	Benign	0.0029	T
PhyloP100		0.47
ClinPred		0.020	T
GERP RS		1.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.10
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141306106; hg19: chr19-49458971;