12-122225996-A-T

Position:

chr12-122225996-A-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001371333.1(DIABLO):c.19T>A(p.Trp7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000663 in 1,603,436 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 1 hom. )

Consequence

DIABLO
NM_001371333.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.51

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10916567).

BP6

Variant 12-122225996-A-T is Benign according to our data. Variant chr12-122225996-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228571.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}. Variant chr12-122225996-A-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIABLO	NM_001371333.1 linkuse as main transcript	c.19T>A	p.Trp7Arg	missense_variant	1/6	ENST00000464942.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIABLO	ENST00000464942.7 linkuse as main transcript	c.19T>A	p.Trp7Arg	missense_variant	1/6	1	NM_001371333.1	P1	Q9NR28-1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000406

AC:

AN:

229004

Hom.:

AF XY:

0.000431

AC XY:

AN XY:

125314

show subpopulations

Gnomad AFR exome

AF:

0.000145

Gnomad AMR exome

AF:

0.0000302

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000345

Gnomad FIN exome

AF:

0.000104

Gnomad NFE exome

AF:

0.000830

Gnomad OTH exome

AF:

0.000527

GnomAD4 exome

AF:

0.000692

AC:

1004

AN:

1451270

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

466

AN XY:

721238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.0000458

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000236

Gnomad4 FIN exome

AF:

0.0000587

Gnomad4 NFE exome

AF:

0.000879

Gnomad4 OTH exome

AF:

0.000350

GnomAD4 genome

AF:

0.000388

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000764

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000768

Hom.:

Bravo

AF:

0.000359

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000699

AC:

ExAC

AF:

0.000438

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	May 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 02, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Trp7Arg varia nt in DIABLO has not been previously reported in individuals with hearing loss, but has been identified in 0.16% (43/27134) European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs139511903). Computational prediction tools and conservation analysis suggest that this varia nt may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p. Trp7Arg variant is uncertain, its frequency in general population suggests that it is more likely to be benign. -

DIABLO-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 25, 2021

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

Uncertain

0.49

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.32

T;T;.;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.59

T;.;T;T

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.6

M;M;M;.

MutationTaster

Benign

1.0

D;D;N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-2.2

N;.;D;.

REVEL

Uncertain

0.51

Sift

Benign

0.12

T;.;T;.

Sift4G

Benign

0.26

T;.;T;.

Polyphen

0.020

B;B;.;.

Vest4

0.60

MutPred

0.82

Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);Gain of disorder (P = 0.005);

MVP

0.68

MPC

0.039

ClinPred

0.048

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.35

gMVP

0.32

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over