NM_138761.4:c.241G>C

Variant names:

• chr19-48956205-G-C
• rs2038122546
• NM_138761.4:c.241G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_138761.4(BAX):​c.241G>C​(p.Ala81Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 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)
• Consequence: BAX NM_138761.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33986247).

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.241G>C	p.Ala81Pro	missense	Exon 4 of 6	NP_620116.1	Q07812-1
	BAX	NM_001291428.2		c.241G>C	p.Ala81Pro	missense	Exon 4 of 6	NP_001278357.1
	BAX	NM_004324.4		c.241G>C	p.Ala81Pro	missense	Exon 4 of 5	NP_004315.1	Q07812-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BAX	ENST00000345358.12	TSL:1 MANE Select	c.241G>C	p.Ala81Pro	missense	Exon 4 of 6	ENSP00000263262.9	Q07812-1
	BAX	ENST00000293288.12	TSL:1	c.241G>C	p.Ala81Pro	missense	Exon 4 of 5	ENSP00000293288.8	Q07812-2
	BAX	ENST00000415969.6	TSL:1	c.241G>C	p.Ala81Pro	missense	Exon 4 of 6	ENSP00000389971.2	Q07812-8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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	Pathogenic	0.97
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		1.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.16
Sift	Benign	0.18	T
Sift4G	Benign	0.27	T
Polyphen		1.0	D
Vest4		0.60
MutPred		0.60		Loss of helix (P = 0.028)
MVP		0.44
MPC		0.67
ClinPred		0.59	D
GERP RS		1.9
Varity_R		0.83
gMVP		0.72
Mutation Taster		=72/28	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: rs2038122546; hg19: chr19-49459462;