12-122224520-T-C

Position:

chr12-122224520-T-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.175A>G(p.Ile59Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

DIABLO
NM_001371333.1 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.896

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=0.023557961).

BP6

Variant 12-122224520-T-C is Benign according to our data. Variant chr12-122224520-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 227299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIABLO	NM_001371333.1 linkuse as main transcript	c.175A>G	p.Ile59Val	missense_variant	2/6	ENST00000464942.7	NP_001358262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIABLO	ENST00000464942.7 linkuse as main transcript	c.175A>G	p.Ile59Val	missense_variant	2/6	1	NM_001371333.1	ENSP00000442360.2		Q9NR28-1
ENSG00000256861	ENST00000535844.1 linkuse as main transcript	n.1595-6123A>G		intron_variant		2		ENSP00000454454.1		H3BMM5

Frequencies

GnomAD3 genomes

AF:

0.000106

AC:

AN:

151320

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000729

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251454

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00120

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000554

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000106

AC:

AN:

151438

Hom.:

Cov.:

AF XY:

0.0000947

AC XY:

AN XY:

73906

show subpopulations

Gnomad4 AFR

AF:

0.0000727

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00175

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.000123

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

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	Oct 25, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2021	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 02, 2015

p.Ile59Val in exon 3 of DIABLO: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, 3 mammals (Star-nosed mole, Egyptian jerboa, bush-tailed rat) have a Valine (Val) at this position despite high nearby amino acid conservation. In addition , computational prediction tools do not suggest a high likelihood of impact to t he protein. This variant has been identified in 0.1% (11/8654) of East Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs574777883). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.28

T;T;.;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.71

T;.;T;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.024

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.94

L;L;L;.

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.41

N;.;N;.

REVEL

Benign

0.13

Sift

Benign

0.55

T;.;T;.

Sift4G

Benign

0.86

T;.;T;.

Polyphen

0.0010

B;B;.;.

Vest4

0.26

MutPred

0.61

Gain of disorder (P = 0.1039);Gain of disorder (P = 0.1039);Gain of disorder (P = 0.1039);Gain of disorder (P = 0.1039);

MVP

0.53

MPC

0.024

ClinPred

0.0093

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.12

gMVP

0.088

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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