NM_138761.4:c.7G>A

Variant names:

• chr19-48954935-G-A
• rs553879570
• NM_138761.4:c.7G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138761.4(BAX):​c.7G>A​(p.Gly3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,089,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: BAX NM_138761.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.49

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAX	NM_138761.4	c.7G>A	p.Gly3Arg	missense_variant	Exon 1 of 6	ENST00000345358.12	NP_620116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAX	ENST00000345358.12	c.7G>A	p.Gly3Arg	missense_variant	Exon 1 of 6	1	NM_138761.4	ENSP00000263262.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000275 AC: 3 AN: 1089538 Hom.: 0 Cov.: 30 AF XY: 0.00000194 AC XY: 1 AN XY: 515960

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: 0.00000325

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	34
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T;.;.;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;N;.;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.85	N;N;N;D;N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;D;D;.;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		1.0	D;D;D;.;D
Vest4		0.30
MutPred		0.14		Loss of glycosylation at S4 (P = 0.0445);Loss of glycosylation at S4 (P = 0.0445);Loss of glycosylation at S4 (P = 0.0445);Loss of glycosylation at S4 (P = 0.0445);Loss of glycosylation at S4 (P = 0.0445);
MVP		0.60
MPC		0.48
ClinPred		0.79	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.5
Varity_R		0.45
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.69		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs553879570; hg19: chr19-49458192;