rs202028496

chr12-122226007-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (2 hom.)
• Consequence: DIABLO NM_001371333.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.25

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]

(HGNC:):

ACMG classification

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 GnomAd at 116 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIABLO	ENST00000464942.7	c.8C>G	p.Ala3Gly	missense_variant	1/6	1	NM_001371333.1	P1

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 116 AN: 152234 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000776 AC XY: 97 AN XY: 124990

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.: 2 Cov.: 32 AF XY: 0.00101 AC XY: 730 AN XY: 721152

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.: 0 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74502

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.: 0

Bravo AF: 0.000842

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000546 AC: 66

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -

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 condition Benign:1

Likely benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;.;.
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.72	T;.;T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.7	L;L;L;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.38	T
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	T
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

Other links and lift over

dbSNP: rs202028496; hg19: chr12-122710554;