rs876657775

Variant names:

• chr12-122218290-A-C
• rs876657775
• NM_001371333.1:c.291T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001371333.1(DIABLO):​c.291T>G​(p.Ile97Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DIABLO NM_001371333.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.520
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant nonsyndromic hearing loss 64

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000256861 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371333.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIABLO	NM_001371333.1	MANE Select	c.291T>G	p.Ile97Met	missense	Exon 3 of 6	NP_001358262.1	A0A0S2Z5U7
	DIABLO	NM_019887.6		c.291T>G	p.Ile97Met	missense	Exon 4 of 7	NP_063940.1	A0A0S2Z5U7
	DIABLO	NM_001278304.2		c.132T>G	p.Ile44Met	missense	Exon 2 of 5	NP_001265233.1	Q9NR28-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIABLO	ENST00000464942.7	TSL:1 MANE Select	c.291T>G	p.Ile97Met	missense	Exon 3 of 6	ENSP00000442360.2	Q9NR28-1
	DIABLO	ENST00000267169.11	TSL:1	c.291T>G	p.Ile97Met	missense	Exon 3 of 7	ENSP00000267169.7	A0A2U3TZH2
	DIABLO	ENST00000353548.11	TSL:1	c.184-1421T>G		intron	N/A	ENSP00000320343.6	Q9NR28-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461832 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.52
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.79	P
Vest4		0.49
MutPred		0.69		Gain of phosphorylation at Y94 (P = 0.2113)
MVP		0.70
MPC		0.088
ClinPred		0.98	D
GERP RS		-0.58
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.40
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs876657775; hg19: chr12-122702837;