12-122218260-A-T

Position:

• chr12-122218260-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001371333.1(DIABLO):​c.315+6T>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000778 in 1,614,092 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 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (1 hom.)
• Consequence: DIABLO NM_001371333.1 splice_donor_region, intron
• Scores: Splicing: ADA: 0.07198
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.631

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 12-122218260-A-T is Benign according to our data. Variant chr12-122218260-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228574.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIABLO	NM_001371333.1	c.315+6T>A		splice_donor_region_variant, intron_variant		ENST00000464942.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIABLO	ENST00000464942.7	c.315+6T>A		splice_donor_region_variant, intron_variant		1	NM_001371333.1	P1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000465 AC: 117 AN: 251396 Hom.: 1 AF XY: 0.000559 AC XY: 76 AN XY: 135872

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000783

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000807 AC: 1180 AN: 1461754 Hom.: 1 Cov.: 31 AF XY: 0.000818 AC XY: 595 AN XY: 727190

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000870

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000947

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000492 AC: 75 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000389 AC XY: 29 AN XY: 74498

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000711 Hom.: 0

Bravo AF: 0.000578

EpiCase AF: 0.000491

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 16, 2016	Variant classified as Uncertain Significance - Favor Benign. The c.315+6T>A vari ant in DIABLO has been reported in the heterozygous state in one individual with hearing loss as well as in one reportedly unaffected parent. It has also been i dentified in 0.05% (57/121370) of chromosomes by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org;dbSNP rs370571609). Although this varian t has been seen in the general population, its frequency is not high enough to r ule out a pathogenic role. This variant is located in the 5' splice region. Comp utational tools do not suggest an impact to splicing; however, this information is not predictive enough to rule out pathogenicity. In summary, while the clinic al significance of the c.315+6T>A variant is uncertain, available data suggest t hat this variant is more likely to be benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 04, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.072
dbscSNV1_RF	Benign	0.25
SpliceAI score (max)		0.010		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: rs370571609; hg19: chr12-122702807;