NM_001371333.1:c.291T>G

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 64

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIABLO	NM_001371333.1	c.291T>G	p.Ile97Met	missense_variant	Exon 3 of 6	ENST00000464942.7	NP_001358262.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIABLO	ENST00000464942.7	c.291T>G	p.Ile97Met	missense_variant	Exon 3 of 6	1	NM_001371333.1	ENSP00000442360.2
ENSG00000256861	ENST00000535844.1	n.*85T>G		non_coding_transcript_exon_variant	Exon 13 of 16	2		ENSP00000454454.1
ENSG00000256861	ENST00000535844.1	n.*85T>G		3_prime_UTR_variant	Exon 13 of 16	2		ENSP00000454454.1

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile97Met variant in DIABLO has not been previously reported in individuals with hearing loss and was absent from large population studies. Computational p rediction tools and conservation analysis do not provide strong support for or a gainst an impact to the protein. In summary, the clinical significance of the p. Ile97Met variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

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;T;D;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T;T;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.0	M;.;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;D;.;.
Polyphen		0.79	P;.;P;.
Vest4		0.49
MutPred		0.69		Gain of phosphorylation at Y94 (P = 0.2113);.;Gain of phosphorylation at Y94 (P = 0.2113);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;