rs4645878

Variant names:

• chr19-48954681-A-G
• rs4645878
• ENST00000812088.1:n.328-4356T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000812088.1(ENSG00000305635):​n.328-4356T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.896 in 383,248 control chromosomes in the GnomAD database, including 154,054 homozygotes. 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: 𝑓 0.89 (60916 hom., cov: 34)
  • Exomes 𝑓: 0.90 (93138 hom.)
• Consequence: ENSG00000305635 ENST00000812088.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.156
• Publications: 64 publications found

Genes affected

ENSG00000305635 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.93 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAX	NM_138761.4	c.-248A>G		upstream_gene_variant		ENST00000345358.12	NP_620116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAX	ENST00000345358.12	c.-248A>G		upstream_gene_variant		1	NM_138761.4	ENSP00000263262.9

Frequencies

GnomAD3 genomes AF: 0.894 AC: 136017 AN: 152162 Hom.: 60868 Cov.: 34

Gnomad AFR AF: 0.909

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.843

Gnomad ASJ AF: 0.914

Gnomad EAS AF: 0.952

Gnomad SAS AF: 0.952

Gnomad FIN AF: 0.922

Gnomad MID AF: 0.911

Gnomad NFE AF: 0.884

Gnomad OTH AF: 0.877

GnomAD4 exome AF: 0.898 AC: 207346 AN: 230968 Hom.: 93138 AF XY: 0.898 AC XY: 105510 AN XY: 117538

African (AFR) AF: 0.915 AC: 5936 AN: 6486

American (AMR) AF: 0.842 AC: 5760 AN: 6838

Ashkenazi Jewish (ASJ) AF: 0.919 AC: 7759 AN: 8440

East Asian (EAS) AF: 0.967 AC: 20708 AN: 21404

South Asian (SAS) AF: 0.955 AC: 2007 AN: 2102

European-Finnish (FIN) AF: 0.925 AC: 19028 AN: 20564

Middle Eastern (MID) AF: 0.905 AC: 1086 AN: 1200

European-Non Finnish (NFE) AF: 0.884 AC: 131526 AN: 148748

Other (OTH) AF: 0.891 AC: 13536 AN: 15186

GnomAD4 genome AF: 0.894 AC: 136124 AN: 152280 Hom.: 60916 Cov.: 34 AF XY: 0.896 AC XY: 66725 AN XY: 74466

African (AFR) AF: 0.909 AC: 37783 AN: 41564

American (AMR) AF: 0.844 AC: 12909 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 3175 AN: 3472

East Asian (EAS) AF: 0.952 AC: 4915 AN: 5164

South Asian (SAS) AF: 0.952 AC: 4594 AN: 4828

European-Finnish (FIN) AF: 0.922 AC: 9787 AN: 10614

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.884 AC: 60120 AN: 68022

Other (OTH) AF: 0.877 AC: 1853 AN: 2112

Alfa AF: 0.888 Hom.: 143545

Bravo AF: 0.887

Asia WGS AF: 0.915 AC: 3183 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.5
DANN	Benign	0.48
PhyloP100		-0.16
PromoterAI		-0.033	Neutral

Splicing

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

Other links and lift over

dbSNP: rs4645878; hg19: chr19-49457938;