chr12-122226007-G-A

Variant names:

• chr12-122226007-G-A
• rs202028496
• NM_001371333.1:c.8C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001371333.1(DIABLO):​c.8C>T​(p.Ala3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIABLO NM_001371333.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36110017).

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.8C>T	p.Ala3Val	missense	Exon 1 of 6	NP_001358262.1	A0A0S2Z5U7
	DIABLO	NM_019887.6		c.8C>T	p.Ala3Val	missense	Exon 2 of 7	NP_063940.1	A0A0S2Z5U7
	DIABLO	NM_001278342.1		c.8C>T	p.Ala3Val	missense	Exon 1 of 5	NP_001265271.1	Q9NR28-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIABLO	ENST00000464942.7	TSL:1 MANE Select	c.8C>T	p.Ala3Val	missense	Exon 1 of 6	ENSP00000442360.2	Q9NR28-1
	DIABLO	ENST00000267169.11	TSL:1	c.8C>T	p.Ala3Val	missense	Exon 1 of 7	ENSP00000267169.7	A0A2U3TZH2
	DIABLO	ENST00000353548.11	TSL:1	c.8C>T	p.Ala3Val	missense	Exon 1 of 5	ENSP00000320343.6	Q9NR28-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451122 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 721154

African (AFR) AF: 0.00 AC: 0 AN: 33282

American (AMR) AF: 0.00 AC: 0 AN: 43690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25834

East Asian (EAS) AF: 0.00 AC: 0 AN: 39378

South Asian (SAS) AF: 0.00 AC: 0 AN: 84872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5322

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107970

Other (OTH) AF: 0.00 AC: 0 AN: 59918

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	0.33
BayesDel_addAF	Benign	-0.0083	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.031
Eigen_PC	Benign	-0.015
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.2
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.22
MutPred		0.28		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.79
MPC		0.12
ClinPred		0.93	D
GERP RS		3.7
PromoterAI		-0.20	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.58
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs202028496; hg19: chr12-122710554;