rs376530914

Variant names:

• chr12-122226025-G-A
• rs376530914
• NM_001371333.1:c.-11C>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.-11C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,601,310 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: DIABLO NM_001371333.1 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.712

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]

ENSG00000256861 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-122226025-G-A is Benign according to our data. Variant chr12-122226025-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228567.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIABLO	NM_001371333.1	c.-11C>T		5_prime_UTR_variant	Exon 1 of 6	ENST00000464942.7	NP_001358262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIABLO	ENST00000464942.7	c.-11C>T		5_prime_UTR_variant	Exon 1 of 6	1	NM_001371333.1	ENSP00000442360.2
ENSG00000256861	ENST00000535844.1	n.1594+6301C>T		intron_variant	Intron 12 of 15	2		ENSP00000454454.1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000218 AC: 49 AN: 225208 Hom.: 0 AF XY: 0.000235 AC XY: 29 AN XY: 123184

Gnomad AFR exome AF: 0.0000737

Gnomad AMR exome AF: 0.000397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000117

Gnomad SAS exome AF: 0.0000349

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.000230 AC: 333 AN: 1448964 Hom.: 0 Cov.: 32 AF XY: 0.000211 AC XY: 152 AN XY: 720086

Gnomad4 AFR exome AF: 0.0000602

Gnomad4 AMR exome AF: 0.000322

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.0000354

Gnomad4 FIN exome AF: 0.0000398

Gnomad4 NFE exome AF: 0.000266

Gnomad4 OTH exome AF: 0.000250

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74496

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000693 Hom.: 0

Bravo AF: 0.000253

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Aug 18, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.-11C>T variant in DIABLO has not been previously reported in individuals w ith hearing loss but has been identified in 22/27112 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs376 530914). This variant is in the 5'UTR of DIABLO; however, its effect on transla tion is unknown. In summary the clinical significance of the c.-3G>T variant is uncertain. -

not provided Benign:1

Oct 02, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.2
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs376530914; hg19: chr12-122710572;