Genetic Variant NM_001188.4:c.125G>A (chr6-33575874-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.40

Variant links:

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]

BAK1 links:

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]

GGNBP1 links:

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ACMG classification

Classification made for transcript

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 link	c.125G>A	p.Arg42His	missense_variant	Exon 3 of 6	ENST00000374467.4	NP_001179.1	Q16611-1A0A0S2Z391

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BAK1	ENST00000374467.4 link	c.125G>A	p.Arg42His	missense_variant	Exon 3 of 6	1	NM_001188.4	ENSP00000363591.3	Q16611-1
BAK1	ENST00000442998.6 link	c.125G>A	p.Arg42His	missense_variant	Exon 3 of 7	1		ENSP00000391258.2	Q16611-2
GGNBP1	ENST00000612409.1 link	n.362+410C>T		intron_variant	Intron 4 of 5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251450

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135900

show subpopulations

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:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727230

show subpopulations

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.:

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

BayesDel_noAF

Benign

-0.48

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

.;.;D

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.78

T;T;T

M_CAP

Benign

0.0086

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.;M

PrimateAI

Uncertain

0.54

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over