rs1051911

Variant names:

• chr6-33575874-C-T
• rs1051911
• NM_001188.4:c.125G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001188.4(BAK1):​c.125G>A​(p.Arg42His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,862 control chromosomes in the GnomAD database, including 1 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000082 (1 hom.)
• Consequence: BAK1 NM_001188.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.40

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2771682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAK1	NM_001188.4	c.125G>A	p.Arg42His	missense_variant	Exon 3 of 6	ENST00000374467.4	NP_001179.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAK1	ENST00000374467.4	c.125G>A	p.Arg42His	missense_variant	Exon 3 of 6	1	NM_001188.4	ENSP00000363591.3
BAK1	ENST00000442998.6	c.125G>A	p.Arg42His	missense_variant	Exon 3 of 7	1		ENSP00000391258.2
GGNBP1	ENST00000612409.1	n.362+410C>T		intron_variant	Intron 4 of 5	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251450 Hom.: 1 AF XY: 0.0000221 AC XY: 3 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461862 Hom.: 1 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.48
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	.;.;D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Benign	0.079
Sift	Benign	0.037	D;D;D
Sift4G	Uncertain	0.033	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.34
MutPred		0.14		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.77
MPC		0.57
ClinPred		0.86	D
GERP RS		2.9
Varity_R		0.43
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1051911; hg19: chr6-33543651; COSMIC: COSV62349604;