6-33575916-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001188.4(BAK1):c.83C>T(p.Ala28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,148 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0020 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (52 hom.)
• Consequence: BAK1 NM_001188.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.22

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004294008).
• BP6: Variant 6-33575916-G-A is Benign according to our data. Variant chr6-33575916-G-A is described in ClinVar as [Benign]. Clinvar id is 707918.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00197 (300/152282) while in subpopulation EAS AF= 0.0282 (146/5184). AF 95% confidence interval is 0.0244. There are 4 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAK1	NM_001188.4	c.83C>T	p.Ala28Val	missense_variant	3/6	ENST00000374467.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAK1	ENST00000374467.4	c.83C>T	p.Ala28Val	missense_variant	3/6	1	NM_001188.4	P1
BAK1	ENST00000442998.6	c.83C>T	p.Ala28Val	missense_variant	3/7	1
GGNBP1	ENST00000612409.1	n.362+452G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152164 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0281

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00477 AC: 1200 AN: 251398 Hom.: 25 AF XY: 0.00506 AC XY: 687 AN XY: 135866

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0349

Gnomad SAS exome AF: 0.0155

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00173 AC: 2525 AN: 1461866 Hom.: 52 Cov.: 31 AF XY: 0.00206 AC XY: 1499 AN XY: 727240

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.0185

Gnomad4 SAS exome AF: 0.0162

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152282 Hom.: 4 Cov.: 31 AF XY: 0.00262 AC XY: 195 AN XY: 74462

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0282

Gnomad4 SAS AF: 0.0205

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00108 Hom.: 7

Bravo AF: 0.00162

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00457 AC: 555

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	18
Dann	Benign	0.97
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.6	L;.;L
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.29	T;T;T
Sift4G	Pathogenic	0.0	D;T;T
Polyphen		0.47	.;.;P
Vest4		0.25
MVP		0.58
MPC		0.39
ClinPred		0.010	T
GERP RS		0.77
Varity_R		0.15
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs4987115; hg19: chr6-33543693; COSMIC: COSV62349759;