rs513349

Positions:

• chr6-33573942-A-G
• chr6-33573942-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001188.4(BAK1):​c.532-35T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,613,490 control chromosomes in the GnomAD database, including 166,392 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. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.51 (21050 hom., cov: 33)
  • Exomes 𝑓: 0.43 (145342 hom.)
• Consequence: BAK1 NM_001188.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.842

Genes affected

BAK1 (HGNC:949): (BCL2 antagonist/killer 1) The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein localizes to mitochondria, and functions to induce apoptosis. It interacts with and accelerates the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c. This protein also interacts with the tumor suppressor P53 after exposure to cell stress. [provided by RefSeq, Jul 2008]

GGNBP1 (HGNC:19427): (gametogenetin binding protein 1 (pseudogene)) This gene is the ortholog of the mouse gametogenetin-binding protein 1 gene. In human, the open reading frame is disrupted by a nonsense mutation after 8-aa; consequently, this gene is currently considered to be a unitary pseudogene in human even though it is functional in other mammals. [provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 2 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAK1	NM_001188.4	c.532-35T>C		intron_variant		ENST00000374467.4	NP_001179.1
BAK1	XM_011514779.4	c.532-35T>C		intron_variant			XP_011513081.1
BAK1	XM_011514780.2	c.355-35T>C		intron_variant			XP_011513082.1
BAK1	XM_047419196.1	c.355-35T>C		intron_variant			XP_047275152.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAK1	ENST00000374467.4	c.532-35T>C		intron_variant		1	NM_001188.4	ENSP00000363591	P1
BAK1	ENST00000442998.6	c.*90-35T>C		intron_variant		1		ENSP00000391258
GGNBP1	ENST00000612409.1	n.249-1409A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77519 AN: 152008 Hom.: 20998 Cov.: 33

Gnomad AFR AF: 0.647

Gnomad AMI AF: 0.533

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.744

Gnomad FIN AF: 0.431

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.513

GnomAD3 exomes AF: 0.513 AC: 128446 AN: 250428 Hom.: 35436 AF XY: 0.520 AC XY: 70395 AN XY: 135388

Gnomad AFR exome AF: 0.653

Gnomad AMR exome AF: 0.512

Gnomad ASJ exome AF: 0.494

Gnomad EAS exome AF: 0.794

Gnomad SAS exome AF: 0.736

Gnomad FIN exome AF: 0.428

Gnomad NFE exome AF: 0.408

Gnomad OTH exome AF: 0.465

GnomAD4 exome AF: 0.432 AC: 630678 AN: 1461364 Hom.: 145342 Cov.: 36 AF XY: 0.441 AC XY: 320802 AN XY: 726998

Gnomad4 AFR exome AF: 0.663

Gnomad4 AMR exome AF: 0.514

Gnomad4 ASJ exome AF: 0.492

Gnomad4 EAS exome AF: 0.717

Gnomad4 SAS exome AF: 0.734

Gnomad4 FIN exome AF: 0.426

Gnomad4 NFE exome AF: 0.384

Gnomad4 OTH exome AF: 0.463

GnomAD4 genome AF: 0.510 AC: 77631 AN: 152126 Hom.: 21050 Cov.: 33 AF XY: 0.520 AC XY: 38694 AN XY: 74372

Gnomad4 AFR AF: 0.647

Gnomad4 AMR AF: 0.525

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.769

Gnomad4 SAS AF: 0.745

Gnomad4 FIN AF: 0.431

Gnomad4 NFE AF: 0.399

Gnomad4 OTH AF: 0.519

Alfa AF: 0.429 Hom.: 28365

Bravo AF: 0.517

Asia WGS AF: 0.723 AC: 2515 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.9
DANN	Benign	0.39
BranchPoint Hunter		2.0

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: rs513349; hg19: chr6-33541719; COSMIC: COSV62349614;