rs202028496

Positions:

chr12-122226007-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001371333.1(DIABLO):c.8C>G(p.Ala3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,603,470 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 2 hom. )

Consequence

DIABLO
NM_001371333.1 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.25

Variant links:

Genes affected

DIABLO (HGNC:21528): (diablo IAP-binding mitochondrial protein) This gene encodes an inhibitor of apoptosis protein (IAP)-binding protein. The encoded mitochondrial protein enters the cytosol when cells undergo apoptosis, and allows activation of caspases by binding to inhibitor of apoptosis proteins. Overexpression of the encoded protein sensitizes tumor cells to apoptosis. A mutation in this gene is associated with young-adult onset of nonsyndromic deafness-64. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

DIABLO links:

ENSG00000256861 (HGNC:):

ENSG00000256861 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013210952).

BP6

Variant 12-122226007-G-C is Benign according to our data. Variant chr12-122226007-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 227298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-122226007-G-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 116 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIABLO	NM_001371333.1 link	c.8C>G	p.Ala3Gly	missense_variant	1/6	ENST00000464942.7	NP_001358262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIABLO	ENST00000464942.7 link	c.8C>G	p.Ala3Gly	missense_variant	1/6	1	NM_001371333.1	ENSP00000442360.2		Q9NR28-1
ENSG00000256861	ENST00000535844.1 link	n.1594+6319C>G		intron_variant		2		ENSP00000454454.1		H3BMM5

Frequencies

GnomAD3 genomes

AF:

0.000762

AC:

116

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000767

AC:

175

AN:

228220

Hom.:

AF XY:

0.000776

AC XY:

AN XY:

124990

show subpopulations

Gnomad AFR exome

AF:

0.000292

Gnomad AMR exome

AF:

0.00166

Gnomad ASJ exome

AF:

0.00126

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000980

Gnomad OTH exome

AF:

0.000881

GnomAD4 exome

AF:

0.00104

AC:

1512

AN:

1451118

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

730

AN XY:

721152

show subpopulations

Gnomad4 AFR exome

AF:

0.000210

Gnomad4 AMR exome

AF:

0.00176

Gnomad4 ASJ exome

AF:

0.00101

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000590

Gnomad4 NFE exome

AF:

0.00121

Gnomad4 OTH exome

AF:

0.000901

GnomAD4 genome

AF:

0.000761

AC:

116

AN:

152352

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00196

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000911

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000872

Hom.:

Bravo

AF:

0.000842

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000546

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2021	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 03, 2017

p.Ala3Gly in exon 2 of DIABLO: This variant is not expected to have clinical sig nificance because it has been identified in various populations with highest fre quencies in 0.16% (54/33120) of Latino chromosomes, 0.12% (12/9630) of Ashkenazi Jewish chromosomes, and 0.11% (107/113660) of European chromosomes by the Genom e Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs20202 8496). -

DIABLO-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;T;.;.

Eigen

Benign

-0.050

Eigen_PC

Benign

-0.070

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.72

T;.;T;T

M_CAP

Pathogenic

0.45

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.7

L;L;L;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.3

N;.;N;.

REVEL

Uncertain

0.37

Sift

Uncertain

0.014

D;.;D;.

Sift4G

Benign

0.11

T;.;T;.

Polyphen

0.99

D;D;.;.

Vest4

0.28

MVP

0.79

MPC

0.083

ClinPred

0.061

GERP RS

3.7

Varity_R

0.11

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over